Research activity information

• 2010 文部科学大臣表彰科学技術賞研究部門


• 2008 大阪市立大学学友会顕彰


• 2007 エルウィン・フォン・ベルツ賞 1等賞


• 1987 エルウィン・フォン・ベルツ賞 2等賞

• Alteration of COX-1 and TLR4 expression in the mouse brain during chronic social defeat stress revealed by Positron Emission Tomography study.

  Yumika Motooka, Ryota Shinohara, Shiho Kitaoka, Ai Uryu, Dongrui Li, Hiroyuki Neyama, Yilong Cui, Tatsuya Kida, Wakiko Arakaki, Hisashi Doi, Yasuyoshi Watanabe, Tomoyuki Furuyashiki

  Despite the recognized roles of neuroinflammation in mental illnesses, PET imaging on currently available biomarkers has limitations due to the lack of evidence demonstrating their relationship to the molecular and cellular events of inflammation associated with the pathology of mental illness. Rodent stress models, such as chronic social defeat stress (SDS), have identified crucial roles for COX-1 and TLR4, which are innate immune molecules, in chronic SDS-induced neuroinflammation and its behavioral consequences. In this study, we performed COX-1 and TLR4 PET imaging at multiple time points during chronic SDS in mice. For COX-1 PET imaging, we used the COX-1 PET probe (S)-[18F]KTP-Me. Subchronic SDS transiently increased uptake and slower washout in broad regions of the brain, including the cerebral cortex, hippocampus, striatum, and thalamus. For TLR4 PET imaging, we developed a new BBB-permeable PET probe, [11C]1, which detected LPS-induced neuroinflammation. Washout of [11C]1 was facilitated in the cerebellum after subchronic and chronic SDS and in the pons-medulla after chronic SDS. Collectively, our findings suggest the potential usefulness of COX-1 and TLR4 PET imaging in visualizing and understanding time-dependent process of neuroinflammation in stress-related mental illnesses.

  Mar. 2025, Journal of pharmacological sciences, 157(3) (3), 156 - 166, English, Domestic magazine

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Modulation of Nicotine-Associated Behaviour in Rats By μ-Opioid Signals from the Medial Prefrontal Cortex to the Nucleus Accumbens Shell

  Feng Zhu, Hirosato Kanda, Hiroyuki Neyama, Yuping Wu, Shigeki Kato, Di Hu, Shaoqi Duan, Koichi Noguchi, Yasuyoshi Watanabe, Kazuto Kobayashi, Yi Dai, Yilong Cui

  Springer Science and Business Media LLC, Jun. 2024, Neuroscience Bulletin

  Scientific journal


• Health Benefits of Electrolyzed Hydrogen Water: Antioxidant and Anti-Inflammatory Effects in Living Organisms

  Di Hu, Shigeru Kabayama, Yasuyoshi Watanabe, Yilong Cui

  Molecular hydrogen, the smallest and lightest molecule, serves as an intense reducing agent. Its distinct characteristics, including minimal size and neutral charge, enhance bioavailability and facilitate significant biological effects. Previously considered physiologically inert, hydrogen has gained recognition as a powerful therapeutic agent, known for its antioxidative and anti-inflammatory properties. Electrolyzed hydrogen water (EHW), enriched with molecular hydrogen, demonstrates remarkable antioxidative capabilities, indicating potential benefits for various diseases. Inflammation-induced reactive oxygen species (ROS) amplify inflammation, leading to secondary oxidative stress and creating a crosstalk between ROS and inflammatory responses. This crosstalk contributes to the pathogenesis and progression of chronic diseases. EHW interrupts this crosstalk, reducing inflammatory cytokines and oxidative stress across various disease models, suggesting therapeutic potential. EHW is also known for its anti-inflammatory effects, extending to pain management, as evidenced in models like sciatic nerve ligation and inflammatory pain. In an inflammatory bowel disease (IBD) model, EHW effectively alleviates abdominal pain, mitigating 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced inflammation and oxidative stress, offering insights for clinical applications. Additionally, hydrogen selectively targets harmful radicals, and EHW intake helps balance stress-induced hormonal dysregulation, potentially easing disorders associated with chronic stress.

  MDPI AG, Mar. 2024, Antioxidants, 13(3) (3), 313 - 313

  Scientific journal


• 脳膠芽腫のコンパニオン診断用PETトレーサーとしての[11C]エリブリンの合成

  丹羽 節, 田原 強, Chase Charles E., Fang Francis G., 中岡 貴義, 入江 さつき, 林中 恵美, 和田 康弘, 向井 英史, 増富 健吉, 渡辺 恭良, 崔 翼龍, 細谷 孝充

  日本分子イメージング学会, Feb. 2024, JSMI Report, 17(1) (1), 30 - 33, Japanese


• 脳膠芽腫のコンパニオン診断用PETトレーサーとしての[11C]エリブリンの合成

  丹羽 節, 田原 強, Chase Charles E., Fang Francis G., 中岡 貴義, 入江 さつき, 林中 恵美, 和田 康弘, 向井 英史, 増富 健吉, 渡辺 恭良, 崔 翼龍, 細谷 孝充

  日本分子イメージング学会, Feb. 2024, JSMI Report, 17(1) (1), 30 - 33, Japanese


• International Nuclear Medicine Consensus on the Clinical Use of Amyloid Positron Emission Tomography in Alzheimer's Disease.

  Mei Tian, Chuantao Zuo, Ali Cahid Civelek, Ignasi Carrio, Yasuyoshi Watanabe, Keon Wook Kang, Koji Murakami, Valentina Garibotto, John O Prior, Henryk Barthel, Yihui Guan, Jiaying Lu, Rui Zhou, Chentao Jin, Shuang Wu, Xiaohui Zhang, Yan Zhong, Hong Zhang

  Alzheimer's disease (AD) is the main cause of dementia, with its diagnosis and management remaining challenging. Amyloid positron emission tomography (PET) has become increasingly important in medical practice for patients with AD. To integrate and update previous guidelines in the field, a task group of experts of several disciplines from multiple countries was assembled, and they revised and approved the content related to the application of amyloid PET in the medical settings of cognitively impaired individuals, focusing on clinical scenarios, patient preparation, administered activities, as well as image acquisition, processing, interpretation and reporting. In addition, expert opinions, practices, and protocols of prominent research institutions performing research on amyloid PET of dementia are integrated. With the increasing availability of amyloid PET imaging, a complete and standard pipeline for the entire examination process is essential for clinical practice. This international consensus and practice guideline will help to promote proper clinical use of amyloid PET imaging in patients with AD.

  Aug. 2023, Phenomics (Cham, Switzerland), 3(4) (4), 375 - 389, English, International magazine

  Scientific journal


• Novel strategy of liver cancer treatment with modified antisense oligonucleotides targeting human vasohibin-2.

  Sachiko Horie, Yasuhiro Suzuki, Tsuyoshi Yamamoto, Satoshi Obika, Kohta Mohri, Chizuru Kiyota, Qin Ren, Shota Warashina, Yasuhiro Wada, Yasuyoshi Watanabe, Hidefumi Mukai, Yasufumi Sato

  Vasohihibin-2 (VASH2) is a homolog of vasohibin-1 (VASH1) and is overexpressed in various cancers. Vasohihibin-2 acts on both cancer cells and cancer microenvironmental cells. Previous analyses have shown that VASH2 promotes cancer progression and abrogation of VASH2 results in significant anticancer effects. We therefore propose VASH2 to be a practical molecular target for cancer treatment. Modifications of antisense oligonucleotide (ASO) such as bridged nucleic acids (BNA)-based modification increases the specificity and stability of ASO, and are now applied to the development of a number of oligonucleotide-based drugs. Here we designed human VASH2-ASOs, selected an optimal one, and developed 2',4'-BNA-based VASH2-ASO. When systemically administered, naked 2',4'-BNA-based VASH2-ASO accumulated in the liver and showed its gene-silencing activity. We then examined the effect of 2',4'-BNA-based VASH2-ASO in liver cancers. Intraperitoneal injection of naked 2',4'-BNA-based VASH2-ASO exerted a potent antitumor effect on orthotopically inoculated human hepatocellular carcinoma cells. The same manipulation also showed potent antitumor activity on the splenic inoculation of human colon cancer cells for liver metastasis. These results provide a novel strategy for the treatment of primary as well as metastatic liver cancers by using modified ASOs targeting VASH2.

  Jul. 2023, Cancer science, English, International magazine

  Scientific journal


• 小型細胞外小胞の肝臓・脾臓取り込み機序解明のためのPET動態解析

  藁科 翔太, 毛利 浩太, 前田 和哉, 和田 康弘, 渡辺 恭良, 向井 英史

  日本DDS学会, Jul. 2023, 日本DDS学会学術集会プログラム予稿集, 39回, 176 - 176, Japanese


• 肝蔵デリバリーに向けたmRNA封入脂質ナノ粒子の遺伝子発現とPET体内動態評価

  毛利 浩太, 宮崎 崇之, 藁科 翔太, 高橋 麻衣子, 仁 欽, 和田 康弘, 渡辺 恭良, 鈴木 裕太, 向井 英史

  日本DDS学会, Jul. 2023, 日本DDS学会学術集会プログラム予稿集, 39回, 181 - 181, Japanese


• Tau accumulates differently in four subtypes of Alzheimer's disease

  Takahito Yoshizaki, Shinobu Minatani, Hiroto Namba, Akitoshi Takeda, Joji Kawabe, Hideko Mizuta, Yasuhiro Wada, Aya Mawatari, Yasuyoshi Watanabe, Hitoshi Shimada, Makoto Higuchi, Yoshiaki Itoh

  Jul. 2023, NEUROLOGY AND CLINICAL NEUROSCIENCE, 11(4) (4), 231 - 238, English

  Scientific journal


• Opioidergic activation of descending pain inhibitory system underlies placebo analgesia

  Hiroyuki Neyama, Yuping Wu, Yuka Nakaya, Shigeki Kato, Tomoko Shimizu, Tsuyoshi Tahara, Mika Shigeta, Michiko Inoue, Kazunari Miyamichi, Natsuki Matsushita, Tomoji Mashimo, Yoshiki Miyasaka, Yasuyoshi Watanabe, Masayuki Kobayashi, Kazuto Kobayashi, Yilong Cui

  Abstract Placebo analgesia is caused by inactive treatment, implicating endogenous brain function involvement. However, the underlying neurobiological mechanisms remain unclear. We found that μ-opioid signals in the medial prefrontal cortex (mPFC) activate the descending pain inhibitory system to initiate placebo analgesia in neuropathic pain rats. Chemogenetic manipulation demonstrated that specific activation of μ-opioid receptor-positive (MOR⁺) neurons in the mPFC or suppression of the mPFC-ventrolateral periaqueductal gray (vlPAG) circuit inhibited placebo analgesia in rats. MOR⁺neurons in the mPFC are monosynaptically connected and directly inhibit L5 pyramidal neurons that project to the vlPAG via GABA_Areceptors. Thus, intrinsic opioid signaling in the mPFC disinhibits excitatory outflow to the vlPAG by suppressing MOR⁺neurons, leading to descending pain inhibitory system activation that initiates placebo analgesia. One Sentence Summary Sugar pills relieve pain by activating the intrinsic pain inhibitory system via opioidergic signals in the prefrontal cortex.

  Cold Spring Harbor Laboratory, Jun. 2023


• Acute nicotine exposure blocks aromatase in the limbic brain of healthy women: A [11C]cetrozole PET study.

  Manon Dubol, Jana Immenschuh, My Jonasson, Kayo Takahashi, Takashi Niwa, Takamitsu Hosoya, Sara Roslin, Johan Wikström, Gunnar Antoni, Yasuyoshi Watanabe, Mark Lubberink, Anat Biegon, Inger Sundström-Poromaa, Erika Comasco

  BACKGROUND: Of interest to women's mental health, a wealth of studies suggests sex differences in nicotine addiction and treatment response, but their psychoneuroendocrine underpinnings remain largely unknown. A pathway involving sex steroids could indeed be involved in the behavioural effects of nicotine, as it was found to inhibit aromatase in vitro and in vivo in rodents and non-human primates, respectively. Aromatase regulates the synthesis of oestrogens and, of relevance to addiction, is highly expressed in the limbic brain. METHODS: The present study sought to investigate in vivo aromatase availability in relation to exposure to nicotine in healthy women. Structural magnetic resonance imaging and two [11C]cetrozole positron emission tomography (PET) scans were performed to assess the availability of aromatase before and after administration of nicotine. Gonadal hormones and cotinine levels were measured. Given the region-specific expression of aromatase, a ROI-based approach was employed to assess changes in [11C]cetrozole non-displaceable binding potential. RESULTS: The highest availability of aromatase was found in the right and left thalamus. Upon nicotine exposure, [11C]cetrozole binding in the thalamus was acutely decreased bilaterally (Cohen's d = -0.99). In line, cotinine levels were negatively associated with aromatase availability in the thalamus, although as non-significant trend. CONCLUSIONS: These findings indicate acute blocking of aromatase availability by nicotine in the thalamic area. This suggests a new putative mechanism mediating the effects of nicotine on human behaviour, particularly relevant to sex differences in nicotine addiction.

  May 2023, Comprehensive psychiatry, 123, 152381 - 152381, English, International magazine

  Scientific journal


• In vitro evaluation of (S)-2-amino-3-[3-(2-18F-fluoroethoxy)-4-iodophenyl]-2-methylpropanoic acid (18F-FIMP) as a positron emission tomography probe for imaging amino acid transporters.

  Satoshi Nozaki, Yuka Nakatani, Aya Mawatari, William Ewan Hume, Hisashi Doi, Yasuyoshi Watanabe

  BACKGROUND: (S)-2-amino-3-[3-(2-18F-fluoroethoxy)-4-iodophenyl]-2-methylpropanoic acid (18F-FIMP) as a promising PET probe for imaging the tumor-specific L-type amino acid transporter (LAT) 1. Our previous study revealed that 18F-FIMP had a higher affinity for LAT1 than for LAT2 abundantly expressed even in normal cells. 18F-FIMP showed high accumulation in LAT1-positive tumor tissues and low accumulation in inflamed lesions in tumor-bearing mice. However, the affinity of 18F-FIMP for other amino acid transporters was not determined yet. Here, we aimed to determine whether 18F-FIMP has affinity for other tumor-related amino acid transporters, such as sodium- and chloride-dependent neutral and basic amino acid transporter B(0 +) (ATB0,+), alanine serine cysteine transporter 2 (ASCT2), and cystine/glutamate transporter (xCT). PROCEDURES: Cells overexpressing LAT1, ATB0,+, ASCT2, or xCT were established by the transfection of expression vectors for LAT1, ATB0,+, ASCT2, or xCT. Protein expression levels were determined by western blot and immunofluorescent analyses. Transport function was evaluated by a cell-based uptake assay using 18F-FIMP and 14C-labeled amino acids as substrates. RESULTS: Intense signals were observed only for expression vector-transfected cells on western blot and immunofluorescent analyses. These signals were strongly reduced by gene-specific small interfering ribonucleic acid treatment. The uptake values for each 14C-labeled substrate were significantly higher in the transfected cells than in the mock-transfected cells and were significantly inhibited by the corresponding specific inhibitors. The 18F-FIMP uptake values were significantly higher in the LAT1- and ATB0,+-overexpressing cells than in the corresponding mock cells, but no such increase was seen in the ASCT2- or xCT-overexpressing cells. These 18F-FIMP uptake values were significantly decreased by the specific inhibitors for LAT1- and ATB0,+. CONCLUSIONS: We demonstrated that 18F-FIMP has affinity not only for LAT1, but also for ATB0,+. Our results may be helpful for understanding the mechanisms of the whole-body distribution and tumor accumulation of 18F-FIMP.

  Apr. 2023, EJNMMI research, 13(1) (1), 36 - 36, English, International magazine

  Scientific journal


• Two-Chain Mature Hepatocyte Growth Factor-Specific Positron Emission Tomography Imaging in Tumors Using 64Cu-Labeled HiP-8, a Nonstandard Macrocyclic Peptide Probe.

  Shota Warashina, Hiroki Sato, Maki Zouda, Maiko Takahashi, Yasuhiro Wada, Toby Passioura, Hiroaki Suga, Yasuyoshi Watanabe, Kunio Matsumoto, Hidefumi Mukai

  Two-chain hepatocyte growth factor (tcHGF), the mature form of HGF, is associated with malignancy and anticancer drug resistance; therefore, its quantification is an important indicator for cancer diagnosis. In tumors, activated tcHGF hardly discharges into the systemic circulation, indicating that tcHGF is an excellent target for molecular imaging using positron emission tomography (PET). We recently discovered HGF-inhibitory peptide-8 (HiP-8) that binds specifically to human tcHGF with nanomolar affinity. The purpose of this study was to investigate the usefulness of HiP-8-based PET probes in human HGF knock-in humanized mice. 64Cu-labeled HiP-8 molecules were synthesized using a cross-bridged cyclam chelator, CB-TE1K1P. Radio-high-performance liquid chromatography-based metabolic stability analyses showed that more than 90% of the probes existed in intact form in blood at least for 15 min. In PET studies, significantly selective visualization of hHGF-overexpressing tumors versus hHGF-negative tumors was observed in double-tumor-bearing mice. The accumulation of labeled HiP-8 into the hHGF-overexpressing tumors was significantly reduced by competitive inhibition. In addition, the radioactivity and distribution of phosphorylated MET/HGF receptor were colocalized in tissues. These results demonstrate that the 64Cu-labeled HiP-8 probes are suitable for tcHGF imaging in vivo, and secretory proteins like tcHGF can be a target for PET imaging.

  Apr. 2023, Molecular pharmaceutics, 20(4) (4), 2029 - 2038, English, International magazine

  Scientific journal


• Synthesis of ¹¹C-Radiolabeled Eribulin as a Companion Diagnostics PET Tracer for Brain Glioblastoma

  Takashi Niwa, Tsuyoshi Tahara, Charles E. Chase, Francis G. Fang, Takayoshi Nakaoka, Satsuki Irie, Emi Hayashinaka, Yasuhiro Wada, Hidefumi Mukai, Kenkichi Masutomi, Yasuyoshi Watanabe, Yilong Cui, Takamitsu Hosoya

  The Chemical Society of Japan, Mar. 2023, Bulletin of the Chemical Society of Japan, 96(3) (3), 283 - 290, English

  Scientific journal


• Characteristic Evaluation of a 11C-Labeled Leucine Analog, l-α-[5-11C]methylleucine, as a Tracer for Brain Tumor Imaging by Positron Emission Tomography.

  Tsuyoshi Tahara, Shuhei Takatani, Mieko Tsuji, Nina Shibata, Nami Hosaka, Michiko Inoue, Masahiro Ohno, Daiki Ozaki, Aya Mawatari, Yasuyoshi Watanabe, Hisashi Doi, Hirotaka Onoe

  Amino acid transporters are upregulated in many cancer cells, and system L amino acid transporters (LAT1-4), in particular, LAT1, which preferentially transports large, neutral, and branched side-chain amino acids, are considered a primary target for cancer positron emission tomography (PET) tracer development. Recently, we developed a 11C-labeled leucine analog, l-α-[5-11C]methylleucine ([5-11C]MeLeu), via a continuous two-step reaction of Pd0-mediated 11C-methylation and microfluidic hydrogenation. In this study, we evaluated the characteristics of [5-11C]MeLeu and also compared the sensitivity to brain tumors and inflammation with l-[11C]methionine ([11C]Met) to determine its potential for brain tumor imaging. Competitive inhibition experiments, protein incorporation, and cytotoxicity experiments of [5-11C]MeLeu were performed in vitro. Further, metabolic analyses of [5-11C]MeLeu were performed using a thin-layer chromatogram. The accumulation of [5-11C]MeLeu in tumor and inflamed regions of the brain was compared with [11C]Met and 11C-labeled (S)-ketoprofen methyl ester by PET imaging, respectively. Transporter assay with various inhibitors revealed that [5-11C]MeLeu is mainly transported via system L amino acid transporters, especially LAT1, into A431 cells. The protein incorporation assay and metabolic assay in vivo demonstrated that [5-11C]MeLeu was neither used for protein synthesis nor metabolized. These results indicate that MeLeu is very stable in vivo. Furthermore, the treatment of A431 cells with various concentrations of MeLeu did not change their viability, even at high concentrations (∼10 mM). In brain tumors, the tumor-to-normal ratio of [5-11C]MeLeu was more elevated than that of [11C]Met. However, the accumulation levels of [5-11C]MeLeu were lower than those of [11C]Met (the standardized uptake value (SUV) of [5-11C]MeLeu and [11C]Met was 0.48 ± 0.08 and 0.63 ± 0.06, respectively). In brain inflammation, no significant accumulation of [5-11C]MeLeu was observed at the inflamed brain area. These data suggested that [5-11C]MeLeu was identified as a stable and safe agent for PET tracers and could help detect brain tumors, which overexpress the LAT1 transporter.

  Mar. 2023, Molecular pharmaceutics, 20(3) (3), 1842 - 1849, English, International magazine

  Scientific journal


• Comparison of [18F]FIMP, [11C]MET, and [18F]FDG PET for early-phase assessment of radiotherapy response.

  Satoshi Nozaki, Yuka Nakatani, Aya Mawatari, Nina Shibata, William E Hume, Emi Hayashinaka, Yasuhiro Wada, Hisashi Doi, Yasuyoshi Watanabe

  Several limitations of [18F]FDG have been reported, such as nonspecific uptake of inflammation foci. Moreover, [11C]MET has been found to accumulate in normal and inflammatory tissues as well as tumors. To increase specificity to tumor tissues, PET probes with tumor-specific molecular targets have been actively developed. [18F]FIMP was found to be highly accumulated in LAT1-positive tumors but not in inflamed tissue. The aim of this study was to explore whether [18F]FIMP can be used for the early-phase evaluation of radiotherapy accompanied by inflammation, and compare its effectiveness with those of [11C]MET and [18F]FDG. Tumor uptake of [18F]FIMP decreased at day 1 after irradiation, and remained low until day 14. Comparatively, that of [18F]FDG initially decreased at day 3 but was transiently elevated at day 7 and then decreased again at day 10. Decreased tumor uptake of [11C]MET was observed at day 10. In line with the uptake of [18F]FIMP, the ratio of Ki-67 immuno-positive cells in tumor tissues significantly decreased at day 1, 7, and 10 as compared with that in the control. These findings suggest that [18F]FIMP may be a PET probe involved in the early detection and prediction of radiotherapy efficacy, although further clarification is needed.

  Feb. 2023, Scientific reports, 13(1) (1), 1961 - 1961, English, International magazine

  Scientific journal


• Impact of tumoral structure and bacterial species on growth and biodistribution of live bacterial therapeutics in xenografted tumours.

  Maiko Takahashi, Erike Widyasari Sukowati, Shoko Nomura, Akari Kato, Kenji Mizuseki, Yasuyoshi Watanabe, Hidefumi Mukai

  Live bacterial therapeutics is gaining attention, especially for cancer therapy, because anaerobic bacteria selectively grow inside the solid tumours. However, the effect of tumour structure and bacterial characteristics on the pharmacokinetics of tumours is unclear; therefore, we aimed to elucidate the effects of tumour structure and types of bacteria on tumoral bacterial growth. Using six mouse xenograft models, including stroma-rich tumours similar to clinical tumours, and two models of live bacterial therapeutics, Salmonella typhimurium VNP20009 and Escherichia coli DH5α, we investigated bacterial growth and distribution in tumours after intravenous administration. Rapid growth of E. coli was observed in HCT116 and other tumours with few collagens, blood vessels not covered by mural cells, and a cancer cell area proliferated disorderly, whereas tumours with contrasting features, such as BxPC-3, showed lower bacterial growth and a limited intratumor distribution. Alternatively, Salmonella typhimurium VNP20009, when successfully proliferated (the probability was approximately 50%), grew to 108 colony forming units/g tissue even in BxPC-3 tumours, and its intratumor distribution was extensive. This study suggests that the development of new methods to modify tumour structure will be essential for the development of anti-tumour clinical therapies based on live bacterial therapeutics.

  Feb. 2023, Journal of drug targeting, 31(2) (2), 194 - 205, English, International magazine

  Scientific journal


• Regional neuroinflammation induced by peripheral infection contributes to fatigue-like symptoms: a [18F]DPA-714 positron emission tomography study in rats.

  Danxi Li, Di Hu, Yuta Ochi, Wakiko Arakaki, Aya Mawatari, Mika Shigeta, Yuping Wu, Emi Hayashinaka, Hiroyuki Neyama, Tsuyoshi Tahara, Yasuhiro Wada, Feng Li, Hisashi Doi, Yasuyoshi Watanabe, Yilong Cui

  INTRODUCTION: A series of symptoms, including fever, widespread pain, fatigue, and even ageusia, have frequently been reported in the context of various infections, such as COVID-19. Although the pathogenic mechanisms underlying an infection causing fever and pain have been well established, the mechanisms of fatigue induced by infection in specific brain regions remain unclear. METHODS: To elucidate whether and how the peripheral infection cause fatigue via regional neuroinflammation, we performed a brain-wide investigation of neuroinflammation in a peripheral pseudoinfection rat model using [18F]DPA-714 positron emission tomography (PET) imaging analysis, in which the polyriboinosinic: polyribocytidylic acid (poly I:C) was intraperitoneally injected. RESULTS: Transient fever lasting for several hours and subsequent suppression of spontaneous activity lasting a few days were induced by poly I:C treatment. Significant increase in plasma interleukin (IL)-1β, IL-6 and tumour necrosis factor (TNF)-α were observed at 2 and 4 h following poly I:C treatment. PET imaging analysis revealed that the brain uptake of [18F]DPA-714 was significantly increased in several brain regions one day after poly I:C treatment, such as the dorsal raphe (DR), parvicellular part of red nucleus (RPC), A5 and A7 noradrenergic nucleus, compared with the control group. The accumulation of [18F]DPA-714 in the DR, RPC and A5 was positively correlated with subsequent fatigue-like behavior, and that in the A7 tended to positively correlate with fever. DISCUSSION: These findings suggest that peripheral infection may trigger regional neuroinflammation, which may cause specific symptoms such as fatigue. A similar mechanism might be involved in COVID-19.

  2023, Frontiers in immunology, 14, 1261256 - 1261256, English, International magazine

  Scientific journal


• The Association between Atherosclerotic Disease Risk Factors and Serum 25-Hydroxyvitamin D Concentration in Japanese Subjects.

  Akane Yasuoka, Naoko Tsugawa, Chihiro Ura, Honami Ogasawara, Kiyoshi Tanaka, Kei Mizuno, Yasuyoshi Watanabe, Akiko Kuwabara

  Recent studies have described that vitamin D deficiency/insufficiency is associated with hypertension, insulin resistance, and dyslipidemia, which are major components of metabolic syndrome causing atherosclerosis. Therefore, we investigated the relationship between serum 25-hydroxyvitamin D [25(OH)D] concentration and atherosclerotic disease risk factors in healthy Japanese adults. In the present cross-sectional study, 1,177 subjects (348 males and 829 females) aged 20-72 y living in Japan (34.7-35.0ºN) were evaluated for vitamin D status by measuring serum 25(OH)D concentration. Atherosclerotic disease risk factors were defined as the presence of two or more of the following three risk factors: high blood pressure, dyslipidemia, and hyperglycemia. The percentages of vitamin D deficient and insufficient subjects were 33% and 46% in males and 59% and 32% in females, respectively. Subjects with atherosclerotic disease risk factors were significantly older and had higher BMI than those without it in both sexes. Male subjects with atherosclerotic disease risk factors had significantly lower physical activity and serum 25(OH)D concentration than those without it. In a logistic regression analysis adjusted for confounding factors, serum 25(OH)D concentration showed a significant inverse association with risk factors of atherosclerotic disease in males (OR=0.951, 95%CI: 0.906-0.998), but not in females. A covariance structure analysis also suggested that serum 25(OH)D level has a direct association with risk factors of atherosclerotic disease. In conclusion, we have demonstrated that low serum 25(OH)D level is a significant factor for increased atherosclerotic disease risk factors in males.

  2023, Journal of nutritional science and vitaminology, 69(3) (3), 176 - 183, English, Domestic magazine

  Scientific journal


• FDG PET Imaging of the Pain Matrix in Neuropathic Pain Model Rats

  Yilong Cui, Hiroyuki Neyama, Di Hu, Tianliang Huang, Emi Hayashinaka, Yasuhiro Wada, Yasuyoshi Watanabe

  Pain is an unpleasant subjective experience that is usually modified by complex multidimensional neuropsychological processes. Increasing numbers of neuroimaging studies in humans have characterized the hierarchical brain areas forming a pain matrix, which is involved in the different dimensions of pain components. Although mechanistic investigations have been performed extensively in rodents, the homologous brain regions involved in the multidimensional pain components have not been fully understood in the rodent brain. Herein, we successfully identified several brain regions activated in response to mechanical allodynia in neuropathic pain rat models using an alternative neuroimaging method based on 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography (FDG PET) scanning. Regions such as the medial prefrontal cortex, primary somatosensory cortex hindlimb region, and the centrolateral thalamic nucleus were identified. Moreover, brain activity in these regions was positively correlated with mechanical allodynia-related behavioral changes. These results suggest that FDG PET imaging in neuropathic pain model rats enables the evaluation of regional brain activity encoding the multidimensional pain aspect. It could thus be a fascinating tool to bridge the gap between preclinical and clinical investigations.

  MDPI AG, Dec. 2022, Biomedicines, 11(1) (1), 63 - 63, English, International magazine

  Scientific journal


• Lasso peptide microcin J25 variant containing RGD motif as a PET probe for integrin αvβ3 in tumor imaging.

  Kohta Mohri, Kim Phuong Huynh Nhat, Maki Zouda, Shota Warashina, Yasuhiro Wada, Yasuyoshi Watanabe, Shunsuke Tagami, Hidefumi Mukai

  Microcin J25 (MccJ25), a lasso peptide, has a unique 3-D interlocked structure that provides high stability under acidic conditions, at high temperatures, and in the presence of proteases. In this study, we generated a positron emission tomography (PET) probe based on MccJ25 analog with an RGD motif and investigated their pharmacokinetics and utility for integrin αvβ3 imaging in tumors. The MccJ25 variant with an RGD motif in the loop region and a lysine substitution at the C-terminus (MccJ25(RGDF)GtoK) was produced in E. coli transfected with plasmid DNA containing the MccJ25 biosynthetic gene cluster (mcjABCD). [64Cu]Cu-MccJ25(RGDF)GtoK was synthesized using the C-terminal lysine labeled with copper-64 (t1/2 = 12.7 h) via a bifunctional chelator; it showed stability in 90% mouse plasma for 45 min. Using PET imaging for integrin αvβ3 positive U87MG tumor bearing mice, [64Cu]Cu-MccJ25(RGDF)GtoK could clearly distinguish the tumor, and its accumulation was significantly higher than that of MccJ25(GIGT)GtoK without the binding motif for integrin αvβ3. Furthermore, MccJ25(RGDF)GtoK enabled visualization of only U87MG tumors but not MCF-7 tumors with low integrin αvβ3 expression in double tumor-bearing mice. In ex vivo biodistribution analysis, the integrin αvβ3 non-specific accumulation of [64Cu]Cu-MccJ25(RGDF)GtoK was significantly lower in various tissues, except for the kidneys, as compared to the control probe ([64Cu]Cu-cyclic RGD peptide). These results of the present study indicate that 64Cu-labeling methods are appropriate for the synthesis of MccJ25-based PET probes, and [64Cu]Cu-MccJ25 variants are useful tools for cancer molecular imaging.

  Nov. 2022, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, 180, 106339 - 106339, English, International magazine

  [Refereed]

  Scientific journal


• Antioxidant effects of continuous intake of electrolyzed hydrogen water in healthy adults.

  Kei Mizuno, Kyosuke Watanabe, Emi Yamano, Kyoko Ebisu, Kanako Tajima, Junzo Nojima, Yusuke Ohsaki, Shigeru Kabayama, Yasuyoshi Watanabe

  Chronic oxidative stress induces deterioration of health and a risk for the onset of various diseases. Previous clinical studies revealed that electrolyzed hydrogen water (EHW) is effective to reduce oxidative stress during hemodialysis in patients with chronic dialysis. In the present observational study, we investigated the antioxidant effects of a daily continuous intake of EHW in healthy adults. The concentrations of serum reactive oxygen metabolites-derived compounds (d-ROMs) and blood urea nitrogen in healthy volunteers (n = 64) who had a habit of intake over 500 mL/day of EHW at least 5 days a week for longer than 6 months were lower than those of age- and sex-matched controls (n = 470) without the habit of EHW intake. Oxidation stress index which the ratio between concentrations in d-ROMs and biological antioxidant potential was correlated with the serum concentration of high-sensitivity C-reactive protein or low-density lipoprotein cholesterol in the EHW group. These results suggest that the continuous intake of EHW induces antioxidant effects and may contribute to alleviate the risk of various oxidative stress-related dysfunctions and diseases in healthy adults.

  Nov. 2022, Heliyon, 8(11) (11), e11853, English, International magazine

  Scientific journal


• Electrolyzed Hydrogen Water Alleviates Abdominal Pain through Suppression of Colonic Tissue Inflammation in a Rat Model of Inflammatory Bowel Disease.

  Di Hu, Tianliang Huang, Mika Shigeta, Yuta Ochi, Shigeru Kabayama, Yasuyoshi Watanabe, Yilong Cui

  Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the digestive tract and is typically accompanied by characteristic symptoms, such as abdominal pain, diarrhea, and bloody stool, severely deteriorating the quality of the patient's life. Electrolyzed hydrogen water (EHW) has been shown to alleviate inflammation in several diseases, such as renal disease and polymyositis/dermatomyositis. To investigate whether and how daily EHW consumption alleviates abdominal pain, the most common symptom of IBD, we examined the antioxidative and anti-inflammatory effects of EHW in an IBD rat model, wherein colonic inflammation was induced by colorectal administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS). We found that EHW significantly alleviated TNBS-induced abdominal pain and tissue inflammation. Moreover, the production of proinflammatory cytokines in inflamed colon tissue was also decreased significantly. Meanwhile, the overproduction of reactive oxygen species (ROS), which is intricately involved in intestinal inflammation, was significantly suppressed by EHW. Additionally, expression of S100A9, an inflammatory biomarker of IBD, was significantly suppressed by EHW. These results suggest that the EHW prevented the overproduction of ROS due to its powerful free-radical scavenging ability and blocked the crosstalk between oxidative stress and inflammation, thereby suppressing colonic inflammation and alleviating abdominal pain.

  Oct. 2022, Nutrients, 14(21) (21), English, International magazine

  Scientific journal


• N-Methylamide-structured SB366791 derivatives with high TRPV1 antagonistic activity: toward PET radiotracers to visualize TRPV1.

  Tatsuya Kida, Nobuaki Takahashi, Masayuki X Mori, Jiacheng H Sun, Hideto Oota, Kosuke Nishino, Takashi Okauchi, Yuta Ochi, Daisuke Kano, Ukihide Tateishi, Yasuyoshi Watanabe, Yilong Cui, Yasuo Mori, Hisashi Doi

  Transient receptor potential cation channel subfamily V member 1 (TRPV1)-targeted compounds were synthesized by modifying the structure of SB366791, a pharmaceutically representative TRPV1 antagonist. To avoid amide-iminol tautomerization, structurally supported N-methylated amides (i.e., 3-alkoxy-substitued N-meythylamide derivatives of SB366791) were evaluated using a Ca2+ influx assay, in which cells expressed recombinant TRPV1 in the presence of 1.0 μM capsaicin. The antagonistic activities of N-(3-methoxyphenyl)-N-methyl-4-chlorocinnamamide (2) (RLC-TV1004) and N-{3-(3-fluoropropoxy)phenyl}-N-methyl-4-chlorocinnamamide (4) (RLC-TV1006) were found to be approximately three-fold higher (IC50: 1.3 μM and 1.1 μM, respectively) than that of SB366791 (IC50: 3.7 μM). These results will help reinvigorate the potential of SB366791 in medicinal chemistry applications. The 3-methoxy and 3-fluoroalkoxy substituents were used to obtain radioactive [11C]methoxy- or [18F]fluoroalkoxy-incorporated tracers for in vivo positron emission tomography (PET). Using the 11C- or 18F-labeled derivatives, explorative PET imaging trials were performed in rats.

  Oct. 2022, RSC medicinal chemistry, 13(10) (10), 1197 - 1204, English, International magazine

  Scientific journal


• 64Cu-labeling of small extracellular vesicle surfaces via a cross-bridged macrocyclic chelator for pharmacokinetic study by positron emission tomography imaging.

  Shota Warashina, Maki Zouda, Kohta Mohri, Yasuhiro Wada, Kazuya Maeda, Yasuyoshi Watanabe, Hidefumi Mukai

  We developed a method of labeling the surfaces of small extracellular vesicles (sEVs) with 64Cu using a cross-bridged, macrocyclic chelator (CB-TE1A1P) and applied to pharmacokinetics study with positron emission tomography (PET). After incubation in 20% plasma for 10 min, approximately a half of the 64Cu was desorbed from 64Cu-labeled sEVs purified by phosphate-buffered saline wash, suggesting partly weak interaction without coordinating to CB-TE1A1P. After subsequent purification with albumin, 64Cu desorption was greatly reduced, resulting in a radiochemical stability of 95.7%. Notably, labeling did not alter the physicochemical and biological properties of sEVs. After intravenous injection, 64Cu-labeled sEVs rapidly disappeared from the systemic blood circulation and accumulated mainly in the liver and spleen of macrophage-competent mice. In macrophage-depleted mice, 64Cu-labeled sEVs remained in the blood circulation for a longer period and gradually accumulated in the liver and spleen, suggesting mechanisms of hepatic and splenic accumulation other than macrophage-dependent phagocytosis. The comparison of tissue uptake clearance between macrophage-competent and macrophage-depleted mice suggests that macrophages contributed to 67% and 76% of sEV uptake in the liver and spleen, respectively. The application of this method in pharmacokinetics PET studies can be useful in preclinical and clinical research and the development of sEV treatment modalities.

  Aug. 2022, International journal of pharmaceutics, 624, 121968 - 121968, English, International magazine

  Scientific journal


• Lysophosphatidic acid receptor type-1 mediates brain activation in micro-positron emission tomography analysis in a fibromyalgia-like mouse model.

  Hiroyuki Neyama, Michiko Nishiyori, Yilong Cui, Yasuyoshi Watanabe, Hiroshi Ueda

  The intermittent cold stress-induced generalized pain response mimics the pathophysiological and pharmacotherapeutic features reported for fibromyalgia patients, including the presence of chronic generalized pain and female dominance. In addition, the intermittent cold stress-induced generalized pain is abolished in lysophosphatidic acid receptor type-1 knockout mice, as reported in many cases of neuropathic pain models. This study aimed to identify the brain loci involved in the intermittent cold stress generalized pain response and test their dependence on the lysophosphatidic acid receptor type-1. Positron emission tomography analyses using 2-deoxy-2-[18 F]fluoro-d-glucose in the presence of a pain stimulus showed that intermittent cold stress causes a significant increase in uptake in the ipsilateral regions, including the salience networking-related anterior cingulate cortex and insular cortex and the cognition-related hippocampus. A significant decrease was observed in the default mode network-related posterior cingulate cortex. Almost these intermittent cold stress-induced changes were abolished in lysophosphatidic acid receptor type-1 knockout mice. There results suggest that the intermittent cold stress-induced generalized pain response is mediated by the lysophosphatidic acid receptor type-1 in specific brain loci related to salience networking and cognition, which may lead to further developments in the treatment of fibromyalgia.

  Aug. 2022, The European journal of neuroscience, 56(3) (3), 4224 - 4233, English, International magazine

  [Refereed]

  Scientific journal


• Regional neuroinflammation caused by peripheral infection is involved in fatigued symptoms: A [18F]DPA-714 PET study

  Yuta Ochi, Di Hu, Danxi Li, Wakiko Arakaki, Aya Mawatari, Mika Shigeta, Yuping Wu, Emi Hayashinaka, Hiroyuki Neyama, Tsuyoshi Tahara, Yasuhiro Wada, Feng Li, Hisashi Doi, Yasuyoshi Watanabe, Yilong Cui

  Abstract A series of symptoms, including fever, widespread pain, fatigue, and even ageusia, have frequently been reported in the context of various infections, such as COVID-19. Although the pathogenic mechanisms underlying an infection causing fever and pain have been well established, the mechanisms of fatigue induced by infection remain unclear. To elucidate whether and how the peripheral infection cause fatigue via regional neuroinflammation, we performed a brain-wide investigation of neuroinflammation in a peripheral pseudoinfection rat model using [¹⁸F]DPA-714 positron emission tomography (PET) imaging analysis, in which the polyriboinosinic: polyribocytidylic acid (poly I:C) was intraperitoneally injected. Consistent with previous reports, transient fever lasting for several hours and subsequent suppression of spontaneous activity lasting a few days were induced by poly I:C treatment. Significant increase in plasma interleukin (IL)-1β, IL-6 and tumour necrosis factor (TNF)-α were observed at 2 and 4 h following poly I:C treatment. PET imaging analysis revealed that the brain uptake of [¹⁸F]DPA-714 was significantly increased in several brain regions one day after poly I:C treatment, such as the dorsal raphe (DR), parvicellular part of red nucleus (RPC), A5 and A7 noradrenergic nucleus, compared with the control group. The accumulation of [¹⁸F]DPA-714 in the DR, RPC and A5 was positively correlated with the fatigue-like behavior, and that in the A7 tended to positively correlate with fever. These findings suggest that peripheral infection may trigger regional neuroinflammation, which may cause specific symptoms such as fatigue. A similar mechanism might be involved in COVID-19.

  Research Square Platform LLC, Jul. 2022


• Computational Study for Amino Acid Production from Carboxylic Acid via ¹⁴C β-decay

  Tomonori Fukuchi, Takashi Niwa, Takamitsu Hosoya, Yasuyoshi Watanabe

  Physical Society of Japan, Jun. 2022, Journal of the Physical Society of Japan, 91(6) (6), English

  [Refereed]

  Scientific journal


• 電解水素水の抗疲労・抗ストレス・抗酸化効果

  渡辺 恭良, 水野 敬, 崔 翼龍, 和田 智之, 高橋 佳代, 水間 広, 渡辺 恭介, 樺山 繁, 森澤 紳勝

  日本疲労学会, Jun. 2022, 日本疲労学会誌, 18(1) (1), 40 - 40, Japanese


• 疲労の慢性化と神経・内分泌・免疫機能の破綻について

  崔 翼龍, 胡 迪, 渡辺 恭良

  日本疲労学会, Jun. 2022, 日本疲労学会誌, 18(1) (1), 42 - 42, Japanese


• Clinical evaluation of [18F]pitavastatin for quantitative analysis of hepatobiliary transporter activity.

  Takayoshi Nakaoka, Ken-Ichi Kaneko, Satsuki Irie, Aya Mawatari, Ami Igesaka, Yuta Uetake, Hidenori Ochiai, Takashi Niwa, Emi Yamano, Yasuhiro Wada, Masaaki Tanaka, Kohei Kotani, Hideki Kawahata, Joji Kawabe, Yukio Miki, Hisashi Doi, Takamitsu Hosoya, Maeda Kazuya, Hiroyuki Kusuhara, Yuichi Sugiyama, Yasuyoshi Watanabe

  It is widely accepted that uptake and efflux transporters on clearance organs play crucial roles in drug disposition. Although in vitro transporter assay system can identify the intrinsic properties of the target transporters, it is not so easy to precisely predict in vivo pharmacokinetic parameters from in vitro data. Positron emission tomography (PET) imaging is a useful tool to directly assess the activity of drug transporters in humans. We recently developed a practical synthetic method for fluorine-18-labeled pitavastatin ([18F]PTV) as a PET probe for quantitative evaluation of hepatobiliary transport. In the present study, we conducted clinical PET imaging with [18F]PTV and compared the pharmacokinetic properties of the probe for healthy subjects with or without rifampicin pretreatment. Rifampicin pretreatment significantly suppressed the hepatic maximum concentration and biliary excretion of the probe to 52% and 34% of the control values, respectively. Rifampicin treatment markedly decreased hepatic uptake clearance (21% of the control), and moderately canalicular efflux clearance with regard to hepatic concentration (52% of the control). These results demonstrate that [18F]PTV is a useful probe for clinical investigation of the activities of hepatobiliary uptake/efflux transporters in humans.

  Jun. 2022, Drug metabolism and pharmacokinetics, 44, 100449 - 100449, English, International magazine

  Scientific journal


• [18F]DPA-714 PET imaging for the quantitative evaluation of early spatiotemporal changes of neuroinflammation in rat brain following status epilepticus.

  Ken-Ichi Kaneko, Satsuki Irie, Aya Mawatari, Ami Igesaka, Di Hu, Takayoshi Nakaoka, Emi Hayashinaka, Yasuhiro Wada, Hisashi Doi, Yasuyoshi Watanabe, Yilong Cui

  BACKGROUND: Most antiepileptic drug therapies are symptomatic and adversely suppress normal brain function by nonspecific inhibition of neuronal activity. In recent times, growing evidence has suggested that neuroinflammation triggered by epileptic seizures might be involved in the pathogenesis of epilepsy. Although the potential effectiveness of anti-inflammatory treatment for curing epilepsy has been extensively discussed, the limited quantitative data regarding spatiotemporal characteristics of neuroinflammation after epileptic seizures makes it difficult to be realized. We quantitatively analyzed the spatiotemporal changes in neuroinflammation in the early phase after status epilepticus in rats, using translocator protein (TSPO) positron emission tomography (PET) imaging, which has been widely used for the quantitative evaluation of neuroinflammation in several animal models of CNS disease. METHODS: The second-generation TSPO PET probe, [18F]DPA-714, was used for brain-wide quantitative analysis of neuroinflammation in the brains of rats, when the status epilepticus was induced by subcutaneous injection of kainic acid (KA, 15 mg/kg) into those rats. A series of [18F]DPA-714 PET scans were performed at 1, 3, 7, and 15 days after status epilepticus, and the corresponding histological changes, including activation of microglia and astrocytes, were confirmed by immunohistochemistry. RESULTS: Apparent accumulation of [18F]DPA-714 was observed in several KA-induced epileptogenic regions, such as the amygdala, piriform cortex, ventral hippocampus, mediodorsal thalamus, and cortical regions 3 days after status epilepticus, and was reversibly displaced by unlabeled PK11195 (1 mg/kg). Consecutive [18F]DPA-714 PET scans revealed that accumulation of [18F]DPA-714 was focused in the KA-induced epileptogenic regions from 3 days after status epilepticus and was further maintained in the amygdala and piriform cortex until 7 days after status epilepticus. Immunohistochemical analysis revealed that activated microglia but not reactive astrocytes were correlated with [18F]DPA-714 accumulation in the KA-induced epileptogenic regions for at least 1 week after status epilepticus. CONCLUSIONS: These results indicate that the early spatiotemporal characteristics of neuroinflammation quantitatively evaluated by [18F]DPA-714 PET imaging provide valuable evidence for developing new anti-inflammatory therapies for epilepsy. The predominant activation of microglia around epileptogenic regions in the early phase after status epilepticus could be a crucial therapeutic target for curing epilepsy.

  Jun. 2022, European journal of nuclear medicine and molecular imaging, 49(7) (7), 2265 - 2275, English, International magazine

  Scientific journal


• Neural correlates of beneficial effects of young plasma treatment in aged mice: PET-SPM analyses and neuro-behavioural/molecular biological studies.

  Kai Zhang, Hiroshi Mizuma, Yuka Nakatani, Yousuke Kanayama, Kayo Takahashi, Yoshino Matsumoto, Yasuhiro Wada, Kayo Onoe, Shino Owada, Emi Hayashinaka, Yuping Wu, Xiaohui Zhang, Mei Tian, Hong Zhang, Yasuyoshi Watanabe

  Apr. 2022, European journal of nuclear medicine and molecular imaging, 49(5) (5), 1456 - 1469, English, International magazine

  Scientific journal


• First-in-human assessment of the novel LAT1 targeting PET probe 18F-FIMP.

  Satoshi Nozaki, Yuka Nakatani, Aya Mawatari, William E Hume, Yasuhiro Wada, Akira Ishii, Masaaki Tanaka, Naohiro Tsuyuguchi, Hisashi Doi, Yasuyoshi Watanabe

  In the first-in-human PET study, we evaluated the biodistribution and tumor accumulation of the novel PET probe, (S)-2-amino-3-[3-(2-18F-fluoroethoxy)-4-iodophenyl]-2-methylpropanoic acid (18F-FIMP), which targets the tumor-related L-type amino acid transporter 1 (LAT1), and compared it with L-[methyl-11C]methionine (11C-MET) and 2-Deoxy-2-18F-fluoro-D-glucose (18F-FDG). 18F-FIMP biodistribution was revealed by whole-body and brain scans in 13 healthy controls. Tumor accumulation of 18F-FIMP was evaluated in 7 patients with a brain tumor, and compared with those of 11C-MET and 18F-FDG. None of the subjects had significant problems due to probe administration, such as adverse effects or abnormal vital signs. 18F-FIMP was rapidly excreted from the kidneys to the urinary bladder. There was no characteristic physiological accumulation in healthy controls. 18F-FIMP PET resulted in extremely clear images in patients with suspected glioblastoma compared with 11C-MET and 18F-FDG. 18F-FIMP could be a useful novel PET probe for LAT1-positive tumor imaging including glioblastoma.

  Mar. 2022, Biochemical and biophysical research communications, 596, 83 - 87, English, International magazine

  Scientific journal


• International consensus on the use of tau PET imaging agent 18F-flortaucipir in Alzheimer's disease.

  Mei Tian, A Cahid Civelek, Ignasi Carrio, Yasuyoshi Watanabe, Keon Wook Kang, Koji Murakami, Valentina Garibotto, John O Prior, Henryk Barthel, Rui Zhou, Haifeng Hou, Xiaofeng Dou, Chentao Jin, Chuantao Zuo, Hong Zhang

  PURPOSE: Positron emission tomography (PET) with the first and only tau targeting radiotracer of 18F-flortaucipir approved by FDA has been increasingly used in depicting tau pathology deposition and distribution in patients with cognitive impairment. The goal of this international consensus is to help nuclear medicine practitioners procedurally perform 18F-flortaucipir PET imaging. METHOD: A multidisciplinary task group formed by experts from various countries discussed and approved the consensus for 18F-flortaucipir PET imaging in Alzheimer's disease (AD), focusing on clinical scenarios, patient preparation, and administered activities, as well as image acquisition, processing, interpretation, and reporting. CONCLUSION: This international consensus and practice guideline will help to promote the standardized use of 18F-flortaucipir PET in patients with AD. It will become an international standard for this purpose in clinical practice.

  Feb. 2022, European journal of nuclear medicine and molecular imaging, 49(3) (3), 895 - 904, English, International magazine

  Scientific journal


• PET imaging of brain aromatase in humans and rhesus monkeys by 11C-labeled cetrozole analogs.

  Kayo Takahashi, Takamitsu Hosoya, Kayo Onoe, Tomoko Mori, Shusaku Tazawa, Aya Mawatari, Yasuhiro Wada, Yumiko Watanabe, Hisashi Doi, Yasuyoshi Watanabe

  Aromatase is an estrogen synthetic enzyme that plays important roles in brain functions. To quantify aromatase expression in the brain by positron emission tomography (PET), we had previously developed [11C]cetrozole, which showed high specificity and affinity. To develop more efficient PET tracer(s) for aromatase imaging, we synthesized three analogs of cetrozole. We synthesized meta-cetrozole, nitro-cetrozole, and iso-cetrozole, and prepared the corresponding 11C-labeled tracers. The inhibitory activities of these three analogs toward aromatase were evaluated using marmoset placenta, and PET imaging of brain aromatase was performed using the 11C-labeled tracers in monkeys. The most promising analog in the monkey study, iso-cetrozole, was evaluated in the human PET study. The highest to lowest inhibitory activity of the analogs toward aromatase in the microsomal fraction from marmoset placenta was in the following order: iso-cetrozole, nitro-cetrozole, cetrozole, and meta-cetrozole. This order showed good agreement with the order of the binding potential (BP) of each 11C-labeled analog to aromatase in the rhesus monkey brain. A human PET study using [11C]iso-analog showed a similar distribution pattern of binding as that of [11C]cetrozole. The time-activity curves showed that elimination of [11C]iso-cetrozole from brain tissue was faster than that of 11C-cetrozole, indicating more rapid metabolism of [11C]iso-cetrozole. [11C]Cetrozole has preferable metabolic stability for brain aromatase imaging in humans, although [11C]iso-cetrozole might also be useful to measure aromatase level in living human brain because of its high binding potential.

  Dec. 2021, Scientific reports, 11(1) (1), 23623 - 23623, English, International magazine

  Scientific journal


• Synthesis of L-[5-11 C]Leucine and L-α-[5-11 C]Methylleucine via Pd0 -mediated 11 C-Methylation and Microfluidic Hydrogenation: Potentiality of Leucine PET Probes for Tumor Imaging.

  Shuhei Takatani, Tsuyoshi Tahara, Mieko Tsuji, Daiki Ozaki, Nina Shibata, Yoshinobu Hashizume, Masaaki Suzuki, Hirotaka Onoe, Yasuyoshi Watanabe, Hisashi Doi

  The efficient synthesis of L-[5-11 C]leucine and L-α-[5-11 C]methylleucine has been investigated using a continuous two-step sequence of rapid reactions consisting of Pd0 -mediated 11 C-methylation and microfluidic hydrogenation. The synthesis of L-[5-11 C]leucine and L-α-[5-11 C]methylleucine was accomplished within 40 min with a decay-corrected radiochemical yield of 15-38 % based on [11 C]CH3 I, radiochemical purity of 95-99 %, and chemical purity of 95-99 %. The Pd impurities in the injectable solution measured using inductively coupled plasma mass spectrometry met the international criteria for human use. Positron emission tomography scanning after an intravenous injection of L-[5-11 C]leucine or L-α-[5-11 C]methyl leucine in A431 tumor-bearing mice was performed. As a result, L-α-[5-11 C]methylleucine was found to be a potentially useful probe for visualizing the tumor. Tissue distribution analysis showed that the accumulation value of L-α-[5-11 C]methylleucine in tumor tissue was high [12±3% injected dose/g tissue (%ID/g)].

  Nov. 2021, ChemMedChem, 16(21) (21), 3271 - 3279, English, International magazine

  Scientific journal


• PET imaging of neural activity, β-amyloid, and tau in normal brain aging.

  Kai Zhang, Hiroshi Mizuma, Xiaohui Zhang, Kayo Takahashi, Chentao Jin, Fahuan Song, Yuanxue Gao, Yousuke Kanayama, Yuping Wu, Yuting Li, Lijuan Ma, Mei Tian, Hong Zhang, Yasuyoshi Watanabe

  Nov. 2021, European journal of nuclear medicine and molecular imaging, 48(12) (12), 3859 - 3871, English, International magazine

  Scientific journal


• International consensus on the use of [18F]-FDG PET/CT in pediatric patients affected by epilepsy.

  Mei Tian, Yasuyoshi Watanabe, Keon Wook Kang, Koji Murakami, Arturo Chiti, Ignasi Carrio, A Cahid Civelek, Jianhua Feng, Yuankai Zhu, Rui Zhou, Shuang Wu, Junming Zhu, Yao Ding, Kai Zhang, Hong Zhang

  PURPOSE: Positron emission tomography (PET) with 18F-fluorodeoxyglucose ([18F]-FDG) has been increasingly applied in precise localization of epileptogenic focus in epilepsy patients, including pediatric patients. The aim of this international consensus is to provide the guideline and specific considerations for [18F]-FDG PET in pediatric patients affected by epilepsy. METHODS: An international, multidisciplinary task group is formed, and the guideline for brain [18F]-FDG PET/CT in pediatric epilepsy patients has been discussed and approved, which include but not limited to the clinical indications, patient preparation, radiopharmaceuticals and administered activities, image acquisition, image processing, image interpretation, documentation and reporting, etc. CONCLUSION: This is the first international consensus and practice guideline for brain [18F]-FDG PET/CT in pediatric epilepsy patients. It will be an international standard for this purpose in clinical practice.

  Nov. 2021, European journal of nuclear medicine and molecular imaging, 48(12) (12), 3827 - 3834, English, International magazine

  Scientific journal


• 疲労の慢性化およびその分子神経メカニズムについて

  崔 翼龍, 胡 迪, 渡辺 恭良

  日本疲労学会, Jul. 2021, 日本疲労学会誌, 17(1) (1), 27 - 27, Japanese


• 慢性疲労動物を用いた疲労の慢性化機序解析

  胡 迪, 李 丹渓, 重田 美香, 越智 祐太, 渡辺 恭良, 崔 翼龍

  日本疲労学会, Jul. 2021, 日本疲労学会誌, 17(1) (1), 30 - 30, Japanese


• 抗疲労・健康と電解水素水

  樺山 繁, 中山 昌明, 崔 翼龍, 渡辺 恭良

  日本疲労学会, Jul. 2021, 日本疲労学会誌, 17(1) (1), 62 - 62, Japanese


• 筋痛性脳脊髄炎/慢性疲労症候群の脳内炎症と病態関連バイオマーカー

  渡辺 恭良, 福田 早苗, 水野 敬, 田中 邦彦, 尾上 嘉代, 和田 康弘, 野島 順三, 中富 康仁, 山口 浩二, 倉恒 弘彦

  日本疲労学会, Jul. 2021, 日本疲労学会誌, 17(1) (1), 35 - 35, Japanese

  [Refereed]

  Scientific journal


• 疲労の慢性化およびその分子神経メカニズムについて

  崔 翼龍, 胡 迪, 渡辺 恭良

  日本疲労学会, Jul. 2021, 日本疲労学会誌, 17(1) (1), 27 - 27, Japanese


• 慢性疲労動物を用いた疲労の慢性化機序解析

  胡 迪, 李 丹渓, 重田 美香, 越智 祐太, 渡辺 恭良, 崔 翼龍

  日本疲労学会, Jul. 2021, 日本疲労学会誌, 17(1) (1), 30 - 30, Japanese


• 抗疲労・健康と電解水素水

  樺山 繁, 中山 昌明, 崔 翼龍, 渡辺 恭良

  日本疲労学会, Jul. 2021, 日本疲労学会誌, 17(1) (1), 62 - 62, Japanese


• Systematic imaging in medicine: a comprehensive review.

  Kai Zhang, Yujie Sun, Shuang Wu, Min Zhou, Xiaohui Zhang, Rui Zhou, Tingting Zhang, Yuanxue Gao, Ting Chen, Yao Chen, Xin Yao, Yasuyoshi Watanabe, Mei Tian, Hong Zhang

  Jun. 2021, European journal of nuclear medicine and molecular imaging, 48(6) (6), 1736 - 1758, English, International magazine

  Scientific journal


• PET imaging of 11C-labeled thiamine tetrahydrofurfuryl disulfide, vitamin B1 derivative: First-in-human study.

  Yasuyoshi Watanabe, Aya Mawatari, Kazuki Aita, Yuzuru Sato, Yasuhiro Wada, Takayoshi Nakaoka, Kayo Onoe, Emi Yamano, Go Akamatsu, Akihito Ohnishi, Keiji Shimizu, Masahiro Sasaki, Hisashi Doi, Michio Senda

  UNLABELLED: Vitamine B1 thiamine is an essential component for glucose metabolism and energy production. The disulfide derivative, thiamine tetrahydrofurfuryl disulfide (TTFD), is more absorbent compared to readily-available water-soluble thiamine salts since it does not require the rate-limiting transport system required for thiamine absorption. However, the detailed pharmacokinetics of thiamine and TTFD under normal and pathological conditions were not clarified yet. Recently, 11C-labeled thiamine and TTFD were synthesized by our group, and their pharmacokinetics were investigated by PET imaging in normal rats. In this study, to clarify the whole body pharmacokinetics of [11C]TTFD in human healthy volunteers, we performed first-in-human PET imaging study with [11C]TTFD, along with radiation dosimetry of [11C]TTFD in humans. METHODS: Synthesis of [11C]TTFD was improved for clinical study. Dynamic whole-body PET images were acquired on three young male normal subjects after intravenous injection of [11C]TTFD. VOIs were defined for source organs on the PET images to measure time-course of [11C]TTFD uptake as percentage injected dose and the number of disintegrations for each organ. Radiation dosimetry was calculated with OLINDA/EXM. RESULTS: We succeeded in developing the improved synthetic method of [11C]TTFD for the first-in-human PET study. In the whole body imaging, uptake of [11C]TTFD by various tissues was almost plateaued at 10 min after intravenous injection, afterward gradually increased for the brain and urinary bladder (urine). %Injected dose was high in the liver, kidney, urinary bladder, heart, spine, brain, spleen, pancreas, stomach, and salivary glands, in this order. %Injected dose per gram of tissue was high also in the pituitary. By dosimetry, the effective radiation dose of [11C]TTFD calculated was 5.5 μSv/MBq (range 5.2-5.7). CONCLUSION: Novel synthetic method enabled clinical PET study with [11C]TTFD, which is a safe PET tracer with a dosimetry profile comparable to other common 11C-PET tracers. Pharmacokinetics of TTFD in the pharmacological dose and at different nutritional states could be further investigated by future quantitative PET studies. Noninvasive in vivo PET imaging for pathophysiology of thiamine-related function may provide diagnostic evidence of novel information about vitamin B1 deficiency in human tissues.

  May 2021, Biochemical and biophysical research communications, 555, 7 - 12, English, International magazine

  Scientific journal


• PET imaging of 11C-labeled thiamine tetrahydrofurfuryl disulfide, vitamin B1 derivative: First-in-human study.

  Yasuyoshi Watanabe, Aya Mawatari, Kazuki Aita, Yuzuru Sato, Yasuhiro Wada, Takayoshi Nakaoka, Kayo Onoe, Emi Yamano, Go Akamatsu, Akihito Ohnishi, Keiji Shimizu, Masahiro Sasaki, Hisashi Doi, Michio Senda

  May 2021, Biochemical and biophysical research communications, 555, 215 - 215, English, International magazine


• 擬似ウイルス感染モデルラットを用いた脳内炎症のPETイメージング

  崔 翼龍, 越智 祐太, 新垣 和貴子, 胡 迪, 李 丹渓, 重田 美香, 和田 康弘, 土居 久志, 渡辺 恭良

  日本分子イメージング学会, May 2021, JSMI Report, 14(2) (2), 126 - 126, Japanese


• 擬似ウイルス感染モデルラットを用いた脳内炎症のPETイメージング

  崔 翼龍, 越智 祐太, 新垣 和貴子, 胡 迪, 李 丹渓, 重田 美香, 和田 康弘, 土居 久志, 渡辺 恭良

  日本分子イメージング学会, May 2021, JSMI Report, 14(2) (2), 126 - 126, Japanese


• Disrupting tumor onset and growth via selective cell tagging (SeCT) therapy.

  Kenward Vong, Tsuyoshi Tahara, Sayaka Urano, Igor Nasibullin, Kazuki Tsubokura, Yoichi Nakao, Almira Kurbangalieva, Hirotaka Onoe, Yasuyoshi Watanabe, Katsunori Tanaka

  Apr. 2021, Science advances, 7(17) (17), English, International magazine

  Scientific journal


• Homeostatic disturbance of thermoregulatory functions in rats with chronic fatigue.

  Danxi Li, Di Hu, Mika Shigeta, Yuta Ochi, Yasuyoshi Watanabe, Feng Li, Yilong Cui

  Chronic fatigue syndrome (CFS) is characterized by long-lasting fatigue, and a range of symptoms, and is involved in homeostasis disruption. CFS patients frequently complain of low grade fever or chill even under normal body temperature indicating that thermosensory or thermoregulatory functions might be disturbed in CFS. However, little is known about the detailed mechanisms. To elucidate whether and how thermoregulatory function was altered during the development of chronic fatigue, we investigated temporal changes in body temperature with advance of fatigue accumulation in a chronic fatigue rat model using a wireless transponder. Our findings demonstrated that the body temperature was adaptively increased in response to fatigue loading in the early phase, but unable to retain in the late phase. The tail heat dissipation was often observed and the frequency of tail heat dissipation gradually increased initially, then decreased. In the late phase of fatigue loading, the body temperature for the tail heat dissipation phase decreased to a value lower than that for the non-dissipation phase. These results suggest that adaptive changes in thermoregulatory function occurred with fatigue progression, but this system might be disrupted by long-lasting fatigue, which may underlie the mechanism of fatigue chronification.

  Apr. 2021, Neuroscience research, 165, 45 - 50, English, International magazine

  [Refereed]

  Scientific journal


• Insights into Metabolite Diagnostic Biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

  Emi Yamano, Yasuyoshi Watanabe, Yosky Kataoka

  Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a persistent and unexplained pathological state characterized by exertional and severely debilitating fatigue, with/without infectious or neuropsychiatric symptoms, and with a minimum duration of 6 consecutive months. Its pathogenesis is not fully understood. There are no firmly established diagnostic biomarkers or treatment, due to incomplete understanding of the etiology of ME/CFS and diagnostic uncertainty. Establishing a biomarker for the objective diagnosis is urgently needed to treat a lot of patients. Recently, research on ME/CFS using metabolome analysis methods has been increasing. Here, we overview recent findings concerning the metabolic features in patients with ME/CFS and the animal models which contribute to the development of diagnostic biomarkers for ME/CFS and its treatment. In addition, we discuss future perspectives of studies on ME/CFS.

  Mar. 2021, International journal of molecular sciences, 22(7) (7), English, International magazine

  Scientific journal


• Alleviation of the chronic stress response attributed to the antioxidant and anti-inflammatory effects of electrolyzed hydrogen water.

  Di Hu, Danxi Li, Mika Shigeta, Yuta Ochi, Takashi Okauchi, Hiroyuki Neyama, Shigeru Kabayama, Yasuyoshi Watanabe, Yilong Cui

  Reactive oxygen species (ROS) are highly reactive and directly attack surrounding biomolecules to deteriorate cellular and tissue functions. Meanwhile, ROS also serve as signaling mediators to upregulate pro-inflammatory cytokine expression via activation of the nuclear factor kappa B signaling pathway, and the increased pro-inflammatory cytokines trigger respiratory burst of inflammatory cells that further accelerates ROS production in the inflamed tissue. Such crosstalk between ROS and inflammatory responses leads to a chain reaction of negativity, and cause progression of several chronic pathologies. Since molecular hydrogen is known to preferentially remove cytotoxic hydroxyl radicals and peroxynitrites, and to prevent cell and tissue damage, we here examined whether electrolyzed hydrogen water (EHW) enriched with molecular hydrogen and reactive hydrogen storing platinum nanoparticles dissolved from an electrode could alleviate oxidative stress and inflammation induced by continuous stress challenges. Five-day continuous stress loading to rats elevated reactive oxygen metabolites-derived compounds (d-ROMs), interleukin (IL)-1β, and adrenocorticotropic hormone (ACTH) levels and decreased the biological antioxidant potential (BAP) level. Drinking EHW during 5-day continuous stress loading significantly alleviated all of these changes. The results suggest that EHW could suppress stress-response-associated oxidative stress and IL-1β level elevation in vivo, and that drinking of EHW is effective for controlling stress responses via its antioxidant potential.

  Jan. 2021, Biochemical and biophysical research communications, 535, 1 - 5, English, International magazine

  Scientific journal


• Review: PET imaging with macro- and middle-sized molecular probes.

  Hidefumi Mukai, Yasuyoshi Watanabe

  Recent progress in radiolabeling of macro- and middle-sized molecular probes has been extending possibilities to use PET molecular imaging for dynamic application to drug development and therapeutic evaluation. Theranostics concept also accelerated the use of macro- and middle-sized molecular probes for sharpening the contrast of proper target recognition even the cellular types/subtypes and proper selection of the patients who should be treated by the same molecules recognition. Here, brief summary of the present status of immuno-PET, and then further development of advanced technologies related to immuno-PET, peptidic PET probes, and nucleic acids PET probes are described.

  Jan. 2021, Nuclear medicine and biology, 92, 156 - 170, English, International magazine

  Scientific journal


• Increase in rear-end collision risk by acute stress-induced fatigue in on-road truck driving.

  Shunsuke Minusa, Kei Mizuno, Daichi Ojiro, Takeshi Tanaka, Hiroyuki Kuriyama, Emi Yamano, Hirohiko Kuratsune, Yasuyoshi Watanabe

  Increasing road crashes related to occupational drivers' deteriorating health has become a social problem. To prevent road crashes, warnings and predictions of increased crash risk based on drivers' conditions are important. However, in on-road driving, the relationship between drivers' physiological condition and crash risk remains unclear due to difficulties in the simultaneous measurement of both. This study aimed to elucidate the relationship between drivers' physiological condition assessed by autonomic nerve function (ANF) and an indicator of rear-end collision risk in on-road driving. Data from 20 male truck drivers (mean ± SD, 49.0±8.2 years; range, 35-63 years) were analyzed. Over a period of approximately three months, drivers' working behavior data, such as automotive sensor data, and their ANF data were collected during their working shift. Using the gradient boosting decision tree method, a rear-end collision risk index was developed based on the working behavior data, which enabled continuous risk quantification. Using the developed risk index and drivers' ANF data, effects of their physiological condition on risk were analyzed employing a logistic quantile regression method, which provides wider information on the effects of the explanatory variables, after hierarchical model selection. Our results revealed that in on-road driving, activation of sympathetic nerve activity and inhibition of parasympathetic nerve activity increased each quantile of the rear-end collision risk index. The findings suggest that acute stress-induced drivers' fatigue increases rear-end collision risk. Hence, in on-road driving, drivers' physiological condition monitoring and ANF-based stress warning and relief system can contribute to promoting the prevention of rear-end truck collisions.

  2021, PloS one, 16(10) (10), e0258892, English, International magazine

  Scientific journal


• Biosorption-based 64Cu-labeling of bacteria for pharmacokinetic positron-emission tomography.

  Shoko Nomura, Maiko Takahashi, Akari Hashiba Kato, Yasuhiro Wada, Yasuyoshi Watanabe, Fumiyoshi Yamashita, Hidefumi Mukai

  Biosorption-based bacterial 64Cu-labeling and its application in pharmacokinetic positron-emission tomography (PET) were investigated. Both gram-positive and gram-negative bacteria were efficiently labeled with [64Cu]Cu2+ ion in saline at room temperature within 5 min. The labeling ratio for Escherichia coli drastically decreased with trypsin pretreatment and the co-presence of excess Cu2+ ion, indicating the existence of specific Cu2+ binding sites on the E. coli cell surface. Washing with lysogeny broth medium was effective in purifying 64Cu-labeled E. coli for kinetic study; the labeling stability was approximately 90% in serum for 15 min. According to dynamic PET imaging in colon-26 tumor-bearing mice, 64Cu-labeled E. coli immediately disappeared from the blood circulation and primarily accumulated in the liver. In addition, transient pulmonary distribution was observed, being in a dose-dependently accelerated manner. Considering the simplicity and versatility of biosorption-based bacterial 64Cu-labeling without genetic modification, the early-phase pharmacokinetic PET with 64Cu-labeled bacteria is promising for assessing toxicological aspects of bacteria-mediated cancer therapy as well as a variety of bacterial pathogenicities in infectious diseases.

  Nov. 2020, International journal of pharmaceutics, 590, 119950 - 119950, English, International magazine

  Scientific journal


• Deep phenotyping of myalgic encephalomyelitis/chronic fatigue syndrome in Japanese population.

  Toshimori Kitami, Sanae Fukuda, Tamotsu Kato, Kouzi Yamaguti, Yasuhito Nakatomi, Emi Yamano, Yosky Kataoka, Kei Mizuno, Yuuri Tsuboi, Yasushi Kogo, Harukazu Suzuki, Masayoshi Itoh, Masaki Suimye Morioka, Hideya Kawaji, Haruhiko Koseki, Jun Kikuchi, Yoshihide Hayashizaki, Hiroshi Ohno, Hirohiko Kuratsune, Yasuyoshi Watanabe

  Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex and debilitating disease with no molecular diagnostics and no treatment options. To identify potential markers of this illness, we profiled 48 patients and 52 controls for standard laboratory tests, plasma metabolomics, blood immuno-phenotyping and transcriptomics, and fecal microbiome analysis. Here, we identified a set of 26 potential molecular markers that distinguished ME/CFS patients from healthy controls. Monocyte number, microbiome abundance, and lipoprotein profiles appeared to be the most informative markers. When we correlated these molecular changes to sleep and cognitive measurements of fatigue, we found that lipoprotein and microbiome profiles most closely correlated with sleep disruption while a different set of markers correlated with a cognitive parameter. Sleep, lipoprotein, and microbiome changes occur early during the course of illness suggesting that these markers can be examined in a larger cohort for potential biomarker application. Our study points to a cluster of sleep-related molecular changes as a prominent feature of ME/CFS in our Japanese cohort.

  Nov. 2020, Scientific reports, 10(1) (1), 19933 - 19933, English, International magazine

  Scientific journal


• Quantification of aromatase binding in the female human brain using [11 C]cetrozole positron emission tomography.

  My Jonasson, Patrik Nordeman, Jonas Eriksson, Helena Wilking, Johan Wikström, Kayo Takahashi, Takashi Niwa, Takamitsu Hosoya, Yasuyoshi Watanabe, Gunnar Antoni, Inger Sundström Poromaa, Mark Lubberink, Erika Comasco

  Aromatase, the enzyme that in the brain converts testosterone and androstenedione to estradiol and estrone, respectively, is a putative key factor in psychoneuroendocrinology. In vivo assessment of aromatase was performed to evaluate tracer kinetic models and optimal scan duration, for quantitative analysis of the aromatase positron emission tomography (PET) ligand [11 C]cetrozole. Anatomical magnetic resonance and 90-min dynamic [11 C]cetrozole PET-CT scans were performed on healthy women. Volume of interest (VOI)-based analyses with a plasma-input function were performed using the single-tissue and two-tissue (2TCM) reversible compartment models and plasma-input Logan analysis. Additionally, the simplified reference tissue model (SRTM), Logan reference tissue model (LRTM), and standardized uptake volume ratio model, with cerebellum as reference region, were evaluated. Parametric images were generated and regionally averaged voxel values were compared with VOI-based analyses of the reference tissue models. The optimal reference model was used for evaluation of a decreased scan duration. Differences between the plasma-input- and reference tissue-based methods and comparisons between scan durations were assessed by linear regression. The [11 C]cetrozole time-activity curves were best described by the 2TCM. SRTM nondisplaceable binding potential (BPND ), with cerebellum as reference region, can be used to estimate [11 C]cetrozole binding and generated robust and quantitatively accurate results for a reduced scan duration of 60 min. Receptor parametric mapping, a basis function implementation of SRTM, as well as LRTM, produced quantitatively accurate parametric images, showing BPND at the voxel level. As PET tracer, [11 C]cetrozole can be employed for relatively short brain scans to measure aromatase binding using a reference tissue-based approach.

  Nov. 2020, Journal of neuroscience research, 98(11) (11), 2208 - 2218, English, International magazine

  Scientific journal


• A Strategy for Tumor Targeting by Higher-Order Glycan Pattern Recognition: Synthesis and In Vitro and In Vivo Properties of Glycoalbumins Conjugated with Four Different N-Glycan Molecules.

  Ivan Smirnov, Regina Sibgatullina, Sayaka Urano, Tsuyoshi Tahara, Peni Ahmadi, Yasuyoshi Watanabe, Ambara R Pradipta, Almira Kurbangalieva, Katsunori Tanaka

  Natural glycoconjugates that form glycocalyx play important roles in various biological processes based on cell surface recognition through pattern recognition mechanisms. This work represents a new synthesis-based screening strategy to efficiently target the cancer cells by higher-order glycan pattern recognition in both cells and intact animals (mice). The use of the very fast, selective, and effective RIKEN click reaction (6π-azaelectrocyclization of unsaturated imines) allows to synthesize and screen various structurally well-defined glycoalbumins containing two and eventually four different N-glycan structures in a very short time. The importance of glycan pattern recognition is exemplified in both cell- and mouse-based experiments. The use of pattern recognition mechanisms for cell targeting represents a novel and promising strategy for the development of diagnostic, prophylactic, and therapeutic agents for various diseases including cancers.

  Nov. 2020, Small (Weinheim an der Bergstrasse, Germany), 16(46) (46), e2004831, English, International magazine

  Scientific journal


• 慢性疲労動物を用いた疲労の慢性化機序の解析

  胡 迪, 李 丹渓, 重田 美香, 岡内 隆, 越智 祐太, 渡辺 恭良, 崔 翼龍

  日本疲労学会, Nov. 2020, 日本疲労学会誌, 16(1) (1), 57 - 57, Japanese


• Effect of Food Containing Paramylon Derived from Euglena gracilis EOD-1 on Fatigue in Healthy Adults: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Trial.

  Takanori Kawano, Junko Naito, Machiko Nishioka, Norihisa Nishida, Madoka Takahashi, Shinichi Kashiwagi, Tomohiro Sugino, Yasuyoshi Watanabe

  Euglena gracilis EOD-1, a kind of microalgae, is known to contain a high proportion of paramylon, a type of β-1,3-glucan. Paramylon derived from E. gracilis EOD-1 is presumed to suppress cellular oxidative injury and expected to reduce fatigue and fatigue sensation. Therefore, we aimed to examine whether food containing paramylon derived from E. gracilis EOD-1 (EOD-1PM) ingestion reduced fatigue and fatigue sensation in healthy adults. We conducted a randomized, double-blind, placebo-controlled, parallel-group comparison study in 66 healthy men and women who ingested a placebo or EOD-1PM daily for 4 weeks (daily life fatigue). Furthermore, at the examination days of 0 and 4 weeks, tolerance to fatigue load was evaluated using mental tasks (task-induced fatigue). We evaluated fatigue sensation using the Visual Analogue Scale, the work efficiency of the advanced trail making test and measured serum antioxidant markers. The EOD-1PM group showed significantly lower levels of physical and mental fatigue sensations and higher levels of work efficiency as well as serum biological antioxidant potential levels than the placebo group. These results indicate that EOD-1PM ingestion reduced fatigue and fatigue sensation, which may be due to an increase in antioxidant potential and maintenance of selective attention during work.

  Oct. 2020, Nutrients, 12(10) (10), English, International magazine

  Scientific journal


• PETによるエクソソームの体内動態評価を指向した膜表面キレーター化学修飾による64Cu標識

  藁科 翔太, 造田 真希, 和田 康弘, 渡辺 恭良, 向井 英史

  (一社)日本核医学会, Oct. 2020, 核医学, 57(Suppl.) (Suppl.), S151 - S151, Japanese


• 生物学的吸着に基づくバクテリア64Cu標識法の菌種適用範囲の検討

  野村 祥子, 高橋 麻衣子, 橋場 月, 和田 康弘, 渡辺 恭良, 向井 英史

  (一社)日本核医学会, Oct. 2020, 核医学, 57(Suppl.) (Suppl.), S151 - S151, Japanese


• 悪性中皮腫特異的マーカーを標的とした抗体PETイメージング

  崔 翼龍, 田原 強, 辻 祥太郎, 仁 欽, 武 玉萍, 井上 美智子, 林中 恵美, 和田 康弘, 渡辺 恭良, 向井 英史, 今井 浩三

  (一社)日本核医学会, Oct. 2020, 核医学, 57(Suppl.) (Suppl.), S172 - S172, Japanese


• 生物学的吸着を応用して64Cu標識した大腸菌の静脈内投与後の体内動態評価

  野村 祥子, 高橋 麻衣子, 橋場 月, 和田 康弘, 渡辺 恭良, 向井 英史

  日本DDS学会, Aug. 2020, 日本DDS学会学術集会プログラム予稿集, 36回, 147 - 147, Japanese


• がん組織イメージングを目的とした64Cu標識lasso peptide MccJ25の作製と体内動態評価

  毛利 浩太, Kim Phuong Huynh Nhat, 造田 真希, 林中 恵美, 和田 康弘, 渡辺 恭良, 田上 俊輔, 向井 英史

  日本DDS学会, Aug. 2020, 日本DDS学会学術集会プログラム予稿集, 36回, 147 - 147, Japanese


• Heavy Tau Burden with Subtle Amyloid β Accumulation in the Cerebral Cortex and Cerebellum in a Case of Familial Alzheimer's Disease with APP Osaka Mutation.

  Hiroyuki Shimada, Shinobu Minatani, Jun Takeuchi, Akitoshi Takeda, Joji Kawabe, Yasuhiro Wada, Aya Mawatari, Yasuyoshi Watanabe, Hitoshi Shimada, Makoto Higuchi, Tetsuya Suhara, Takami Tomiyama, Yoshiaki Itoh

  We previously identified a novel mutation in amyloid precursor protein from a Japanese pedigree of familial Alzheimer's disease, FAD (Osaka). Our previous positron emission tomography (PET) study revealed that amyloid β (Aβ) accumulation was negligible in two sister cases of this pedigree, indicating a possibility that this mutation induces dementia without forming senile plaques. To further explore the relationship between Aβ, tau and neurodegeneration, we performed tau and Aβ PET imaging in the proband of FAD (Osaka) and in patients with sporadic Alzheimer's disease (SAD) and healthy controls (HCs). The FAD (Osaka) patient showed higher uptake of tau PET tracer in the frontal, lateral temporal, and parietal cortices, posterior cingulate gyrus and precuneus than the HCs (>2.5 SD) and in the lateral temporal and parietal cortices than the SAD patients (>2 SD). Most noticeably, heavy tau tracer accumulation in the cerebellum was found only in the FAD (Osaka) patient. Scatter plot analysis of the two tracers revealed that FAD (Osaka) exhibits a distinguishing pattern with a heavy tau burden and subtle Aβ accumulation in the cerebral cortex and cerebellum. These observations support our hypothesis that Aβ can induce tau accumulation and neuronal degeneration without forming senile plaques.

  Jun. 2020, International journal of molecular sciences, 21(12) (12), English, International magazine


• Ubiquinol-10 Intake Is Effective in Relieving Mild Fatigue in Healthy Individuals.

  Kei Mizuno, Akihiro T Sasaki, Kyosuke Watanabe, Yasuyoshi Watanabe

  Our double-blind, placebo-controlled study evaluated effects of ubiquinol, the reduced form of coenzyme Q10, on mild fatigue in healthy individuals experiencing fatigue in daily life that had continued for more than 1 and less than 6 months. The participants received 100-mg/day (Ubq100; age 44.0 ± 9.8 years; 14 females and 6 males) or 150-mg/day ubiquinol (Ubq150; age 40.4 ± 11.8 years; 14 females and 8 males) or placebo (Plc; age 41.3 ± 13.4 years; 13 females and 7 males) daily for 12 weeks. Measurements of subjective and objective fatigue were conducted by using questionnaires-based fatigue scales/visual analogue scales and autonomic nerve function/biological oxidation index, respectively, prior to the first dosing and every 4 weeks thereafter. Serum ubiquinol level increased three- to four-fold after 4 weeks and remained significantly higher than that after Plc administration throughout the intake period. Although a higher blood level of ubiquinol was observed with Ubq150 than with Ubq100, the difference was not statistically significant. In both Ubq100 and Ubq150 groups, subjective levels of fatigue sensation and sleepiness after cognitive tasks, which consisted of the modified Advanced Trail Making Test, the modified Stroop Color-Word Test, and the Digit Symbol Substitution Test, improved significantly compared with those in the placebo group, suggesting an anti-fatigue effect. The Ubq150 group demonstrated significant improvement compared with the Plc group regarding subjective level of relaxation after task, sleepiness before and after task, motivation for task, and serum level of oxidative stress. Correlation analysis between blood level of ubiquinol and each evaluated effect suggested a positive relationship with relaxation after task, motivation for cognitive task, and parasympathetic activity. The results of the study suggest that ubiquinol intake relieves mild fatigue in healthy individuals.

  Jun. 2020, Nutrients, 12(6) (6), English, International magazine

  Scientific journal


• Practical Synthesis of [18F]Pitavastatin and Evaluation of Hepatobiliary Transport Activity in Rats by Positron Emission Tomography

  Takayoshi Nakaoka, Yuta Uetake, Ken-ichi Kaneko, Takashi Niwa, Hidenori Ochiai, Satsuki Irie, Yoshie Suezaki, Natsumi Otsuka, Emi Hayashinaka, Yasuhiro Wada, Yilong Cui, Kazuya Maeda, Hiroyuki Kusuhara, Yuichi Sugiyama, Takamitsu Hosoya, Yasuyoshi Watanabe

  We developed a practical synthetic method for fluorine-18 (18F)-labeled pitavastatin ([18F]PTV) as a positron emission tomography (PET) tracer to assess hepatobiliary transporter activity and conducted a PET scan as a preclinical study for proof-of-concept in rats. This method is a one-pot synthesis involving aromatic 18F-fluorination of an arylboronic acid ester followed by deprotection under acidic conditions, which can be reproduced in general clinical sites equipped with a standard radiolabeling system due to the simplified procedure. PET imaging confirmed that intravenously administered [18F]PTV was rapidly accumulated in the liver and gradually transferred into the intestinal lumen through the bile duct. Radiometabolite analysis showed that [18F]PTV was metabolically stable, and 80% of the injected dose was detected as the unchanged form in both blood and bile. We applied integration plot analysis to assess tissue uptake clearance (CLuptake, liver and CLuptake, kidney) and canalicular efflux clearance (CLint, bile), and examined the effects of inhibitors on membrane transport. Treatment with rifampicin, an organic anion transporting polypeptide inhibitor, significantly reduced CLuptake, liver and CLuptake, kidney to 44% and 64% of control, respectively. In contrast, Ko143, a breast cancer resistance protein inhibitor, did not affect CLuptake, liver but significantly reduced CLint, bile to 39% of control without change in [18F]PTV blood concentration. In addition, we found decreased CLuptake, liver and increased CLint, bile in Eisai hyperbilirubinemic rats in response to altered expression levels of transporters. We expect that [18F]PTV can be translated into clinical application, as our synthetic method does not need special apparatus in the radiolabeling system and PET scan with [18F]PTV can quantitatively evaluate transporter activity in vivo.

  American Chemical Society (ACS), Jun. 2020, Molecular Pharmaceutics, 17(6) (6), 1884 - 1898, English, International magazine

  [Refereed]

  Scientific journal


• がんプレシジョン診断を目的とした環状ペプチドプローブによる活性型HGF選択的PETイメージング

  藁科 翔太, 佐藤 拓輝, 造田 真希, 酒井 克也, Passioura Toby, 和田 康弘, 菅 裕明, 松本 邦夫, 渡辺 恭良, 向井 英史

  日本分子イメージング学会, May 2020, JSMI Report, 13(2) (2), 37 - 37, Japanese


• Integrin αvβ3高発現がん組織イメージングを目的としたRGD配列を挿入したlasso peptide MccJ25のPETプローブとしての有用性評価

  毛利 浩太, Huynh Nhat Kim Phuong, 造田 真希, 林中 恵美, 和田 康弘, 渡辺 恭良, 田上 俊輔, 向井 英史

  日本分子イメージング学会, May 2020, JSMI Report, 13(2) (2), 30 - 30, Japanese


• 銅(II)イオンの生物学的吸着を利用した細菌の64Cu標識

  野村 祥子, 高橋 麻衣子, 橋場 月, 和田 康弘, 渡辺 恭良, 向井 英史

  日本分子イメージング学会, May 2020, JSMI Report, 13(2) (2), 33 - 33, Japanese


• Cancer discrimination by on-cell N-glycan ligation.

  Shogo Nomura, Yasuko Egawa, Sayaka Urano, Tsuyoshi Tahara, Yasuyoshi Watanabe, Katsunori Tanaka

  In the field of molecular imaging, selectivity for target cells is a key determinant of the degree of imaging contrast. Previously, we developed a pre-targeted method by which target cells could be selectively imaged using a labeled N-glycan that was ligated in situ with an integrin-targeted cyclic RGD peptide on the cell surface. Here we demonstrate the power of our method in discriminating various cancerous and non-cancerous cells that cannot be distinguished using conventional RGD ligands. Using four cyclic RGDyK peptides with various linker lengths with five N-glycans, we identify optimal combinations to discriminate six types of αvβ3 integrin-expressing cells on 96-well plates. The optimal combinations of RGD and N-glycan ligands for the target cells are fingerprinted on the plates, and then used to selectively image tumors in xenografted mouse models. Using this method, various N-glycan molecules, even those with millimolar affinities for their cognate lectins, could be used for selective cancer cell differentiation.

  Feb. 2020, Communications chemistry, 3(1) (1), 26 - 26, English, International magazine

  Scientific journal


• Beta-ray imaging system with γ-ray coincidence for multiple-tracer imaging.

  Tomonori Fukuchi, Seiichi Yamamoto, Jun Kataoka, Kei Kamada, Akira Yoshikawa, Yasuyoshi Watanabe, Shuichi Enomoto

  PURPOSE: Beta-ray imaging systems are widely used for various biological objects to obtain a two-dimensional (2D) distribution of β-ray emitting radioisotopes. However, a conventional β-ray imaging system is unsuitable for multiple-tracer imaging, because the continuous energy distribution of β-rays complicates distinguishing among different tracers by energy information. Therefore, we developed a new type of β-ray imaging system, which is useful for multiple tracers by detecting coincidence γ-rays with β-rays, and evaluated its imaging performance. METHODS: Our system is composed of position-sensitive β-ray and γ-ray detectors. The former is a 35 × 35 × 1-mm3 Ce-Doped((La, Gd)2 Si2 O7 ) (La-GPS) scintillation detector, which has a 300-µm pitch of pixels. The latter is a 43 × 43 × 16-mm3 bismuth germanium oxide (BGO) scintillation detector. Both detectors are mounted on a flexible frame and placed in a user-selectable position. We experimentally evaluated the performance of the β-ray detector and the γ-ray efficiencies of the γ-ray detector with different energies, positions, and distances. We also conducted point sources and phantom measurements with dual isotopes to evaluate the system performance of multiple-tracer imaging. RESULTS: For the β-ray detector, the β-ray detection efficiencies for 45 Ca (245-keV maximum energy) and 90 Sr/90 Y (545 and 2280-keV maximum energy) were 14.3% and 21.9%, respectively. The total γ-ray detection efficiency of the γ-ray detector for all γ-rays from 22 Na (511-keV annihilation γ-rays and a 1275-keV γ-ray) in the center position with a detector distance of 20 mm was 17.5%. From a point-source measurement using 22 Na and 90 Sr/90 Y, we successfully extracted the position of a positron-γ emitter 22 Na. Furthermore, for a phantom experiment using 45 Ca and 18 F or 18 F and 22 Na, we successfully extracted the distribution of the second tracer using the annihilation γ-ray or de-excitation γ-ray coincidence. In all the imaging experiments, the event counts of the extracted images were consistent with the counts estimated by the measured γ-ray efficiencies. CONCLUSIONS: We successfully demonstrated the feasibility of our β-ray autoradiography system for imaging multiple isotopes. Since our system can identify not only a β-γ emitter but also a positron emitter using the coincidence detection of annihilation γ-rays, it is useful for PET tracers and various new applications that are otherwise impractical.

  Feb. 2020, Medical physics, 47(2) (2), 587 - 596, English, International magazine

  Scientific journal


• Relationship between truck driver fatigue and rear-end collision risk.

  Kei Mizuno, Daichi Ojiro, Takeshi Tanaka, Shunsuke Minusa, Hiroyuki Kuriyama, Emi Yamano, Hirohiko Kuratsune, Yasuyoshi Watanabe

  The fatigue of truck, bus, and taxi drivers has been a causal trigger for road accidents. However, the relationship between collision risk and the extent of objective fatigue has yet to be confirmed. In this study, we aimed to identify the relationship between autonomic nerve function as an objective parameter of fatigue and the extent of rear-end collision risk, which includes not only objectively risky events but also situations in which truck drivers require safety guidance from safety transport managers. Data of 33 truck driver participants (2 females, 31 males, 46.0 ± 9.1 years old, min-max: 24-65 years old) were analyzed. Drive recorder and automotive sensor data were collected over an eight-month period, and the autonomic nerve function during resting state in drivers was evaluated daily, pre- and post-shift, using pulse waves and electrocardiographic waveform measurement. The rear-end collision risk Index was developed using decision tree analysis of the audiovisual drive recorder data and distance data from the front automotive sensors. The rear-end collision risk index of shift-day was positively correlated with the sympathetic nerve activity index of post-shift condition on the previous day. This suggests that fatigue-related sympathetic nerve overactivity of post-shift condition increases the rear-end collision risk in the following day. Measures, such as actively seeking rest and undertaking fatigue recovery according to the degree of sympathetic nerve activity of post-shift condition, are necessary in order to prevent truck drivers' rear-end collisions.

  2020, PloS one, 15(9) (9), e0238738, English, International magazine

  Scientific journal


• Pain matrix shift in the rat brain following persistent colonic inflammation revealed by voxel-based statistical analysis

  Tianliang Huang, Takashi Okauchi, Di Hu, Mika Shigeta, Yuping Wu, Yasuhiro Wada, Emi Hayashinaka, Shenglan Wang, Yoko Kogure, Koichi Noguchi, Yasuyoshi Watanabe, Yi Dai, Yilong Cui

  Nov. 2019, MOLECULAR PAIN, 15, 1744806919891327 - 1744806919891327, English, International magazine

  [Refereed]

  Scientific journal


• Identification of actin network proteins, talin-1 and filamin-A, in circulating extracellular vesicles as blood biomarkers for human myalgic encephalomyelitis/chronic fatigue syndrome.

  Eguchi A, Fukuda S, Kuratsune H, Nojima J, Nakatomi Y, Watanabe Y, Feldstein AE

  Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious, debilitating disorder with a wide spectrum of symptoms, including pain, depression, and neurocognitive deterioration. Over 17 million people around the world have ME/CFS, predominantly women with peak onset at 30-50 years. Given the wide spectrum of symptoms and unclear etiology, specific biomarkers for diagnosis and stratification of ME/CFS are lacking. Here we show that actin network proteins in circulating extracellular vesicles (EVs) offer specific non-invasive biomarkers for ME/CFS. We found that circulating EVs were significantly increased in ME/CFS patients correlating to C-reactive protein, as well as biological antioxidant potential. Area under the receiver operating characteristic curve for circulating EVs was 0.80, allowing correct diagnosis in 90-94% of ME/CFS cases. From two independent proteomic analyses using circulating EVs from ME/CFS, healthy controls, idiopathic chronic fatigue, and depression, proteins identified from ME/CFS patients are involved in focal adhesion, actin skeletal regulation, PI3K-Akt signaling pathway, and Epstein-Barr virus infection. In particular, talin-1, filamin-A, and 14-3-3 family proteins were the most abundant proteins, representing highly specific ME/CFS biomarkers. Our results identified circulating EV number and EV-specific proteins as novel biomarkers for diagnosing ME/CFS, providing important information on the pathogenic mechanisms of ME/CFS.

  Nov. 2019, Brain, behavior, and immunity, 84, 106 - 114, English, International magazine

  [Refereed]

  Scientific journal


• 18F-FIMP: a LAT1-specific PET probe for discrimination between tumor tissue and inflammation.

  Satoshi Nozaki, Yuka Nakatani, Aya Mawatari, Nina Shibata, William E Hume, Emi Hayashinaka, Yasuhiro Wada, Hisashi Doi, Yasuyoshi Watanabe

  Positron emission tomography (PET) imaging can assist in the early-phase diagnostic and therapeutic evaluation of tumors. Here, we report the radiosynthesis, small animal PET imaging, and biological evaluation of a L-type amino acid transporter 1 (LAT1)-specific PET probe, 18F-FIMP. This probe demonstrates increased tumor specificity, compared to existing tumor-specific PET probes (18F-FET, 11C-MET, and 18F-FDG). Evaluation of probes by in vivo PET imaging, 18F-FIMP showed intense accumulation in LAT1-positive tumor tissues, but not in inflamed lesions, whereas intense accumulation of 18F-FDG was observed in both tumor tissues and in inflamed lesions. Metabolite analysis showed that 18F-FIMP was stable in liver microsomes, and mice tissues (plasma, urine, liver, pancreas, and tumor). Investigation of the protein incorporation of 18F-FIMP showed that it was not incorporated into protein. Furthermore, the expected mean absorbed dose of 18F-FIMP in humans was comparable or slightly higher than that of 18F-FDG and indicated that 18F-FIMP may be a safe PET probe for use in humans. 18F-FIMP may provide improved specificity for tumor diagnosis, compared to 18F-FDG, 18F-FET, and 11C-MET. This probe may be suitable for PET imaging for glioblastoma and the early-phase monitoring of cancer therapy outcomes.

  Oct. 2019, Scientific reports, 9(1) (1), 15718 - 15718, English, International magazine

  Scientific journal


• Integrated Imaging on Fatigue and Chronic Fatigue

  Yasuyoshi Watanabe, Masaaki Tanaka, Akira Ishii, Kei Mizuno, Akihiro Sasaki, Emi Yamano, Yilong Cui, Sanae Fukuda, Yosky Kataoka, Kozi Yamaguti, Yasuhito Nakatomi, Yasuhiro Wada, Hirohiko Kuratsune

  Springer Singapore, Oct. 2019, Make Life Visible, 227 - 233

  In book


• Quantitative investigation of hepatobiliary transport of [11C]telmisartan in humans by PET imaging.

  Kazuya Maeda, Akihito Ohnishi, Masahiro Sasaki, Yasuhiko Ikari, Kazuki Aita, Yasuyoshi Watanabe, Hiroyuki Kusuhara, Yuichi Sugiyama, Michio Senda

  The pharmacokinetics of telmisartan are nonlinear within the clinical dose range. To identify the underlying mechanism of this nonlinearity, we conducted a PET study in healthy subjects using [11C]telmisartan. Eight healthy male subjects were enrolled in a 2-way crossover study. PET imaging was performed after intravenous administration of [11C]telmisartan with or without a 1-h oral predose of two 40 mg Micardis® tablets. About 60% of the injected [11C]telmisartan accumulated in the liver within 10 min after injection. With predosing of 80 mg telmisartan, the systemic elimination of [11C]telmisartan was slightly delayed, but the liver exposure started to decrease earlier and biliary excretion was greatly enhanced. Hepatic uptake clearance of the radioactivity was not changed by telmisartan predosing, whereas the biliary clearance of radioactivity from the liver was significantly increased. Thus, the alteration in the pharmacokinetics of the radioactivity could not be explained simply by the saturation of hepatic uptake. Therefore, other mechanisms, such as the saturation of intracellular binding of telmisartan and/or its glucuronide, and the glucuronidation of telmisartan by uridine 5'-diphospho-glucuronosyltransferases, should be considered. This is the first reported human PET study using [11C]telmisartan, the results of which can assist understanding of the hepatobiliary transport of telmisartan in humans.

  Oct. 2019, Drug metabolism and pharmacokinetics, 34(5) (5), 293 - 299, English, International magazine

  Scientific journal


• 【トランスポーターのすべて】トランスポーターが関連する疾患研究 PET分子イメージング活用創薬 ヒトでの薬物動態を中心に

  渡辺 恭良, 向井 英史

  医歯薬出版(株), Oct. 2019, 医学のあゆみ, 271(1) (1), 49 - 56, Japanese

  [Refereed]

  Scientific journal


• A simple questionnaire for the prediction of vitamin D deficiency in Japanese adults (Vitaimn D Deficiency questionnaire for Japanese: VDDQ-J).

  Akiko Kuwabara, Naoko Tsugawa, Kei Mizuno, Honami Ogasawara, Yasuyoshi Watanabe, Kiyoshi Tanaka

  Vitamin D deficiency (VDD) is associated with an increased risk of various diseases. Serum 25-hydroxyvitamin D [25(OH)D] concentration is the best marker for vitamin D status and its concentration < 20 ng/mL indicates VDD. However, its measurement is not easily applicable for the evaluation of vitamin D status in the general population because of its cost. Therefore, we aimed to develop a simple questionnaire for easily identifying the risk of VDD. From the total sample (649 healthy subjects aged 19-70 years), 434 and 215 subjects were randomly assigned to the derivation and the validation cohort, respectively. Prediction model for VDD was developed by backward logistic regression analysis. The regression β coefficients of the significant predictors were transformed into integral numbers and used for the individual score. These individual scores were summed to calculate the total risk score (VDD questionnaire for Japanese score: VDDQ-J score). VDD was present in 54.1% of the total subjects. The model for the prediction of VDD consisted of 7 predictors. Areas under the curve were 0.78 and 0.75 in the data set of internal validation and of the external validation, respectively. The cutoff value was determined to be 31 points (range 0-54) with the sensitivity/specificity and positive predictive value/negative predictive value of 61%/79%, and 81%/57%, respectively. Our VDDQ-J score is easy to answer by the wide range of subjects, and well predicts VDD. This risk score would be useful to identify subjects at risk for VDD both in clinical and epidemiological settings.

  Sep. 2019, Journal of bone and mineral metabolism, 37(5) (5), 854 - 863, English, Domestic magazine

  Scientific journal


• 環状ペプチドによるHGF阻害と高速原子間力顕微鏡による分子動態計測

  酒井 克也, 佐藤 拓輝, 柴田 幹大, 高木 淳一, 加藤 幸成, 向井 英史, 渡辺 恭良, 矢野 聖二, 管 裕明, 松本 邦夫

  (公社)日本生化学会, Sep. 2019, 日本生化学会大会プログラム・講演要旨集, 92回, [2T09a - 03], Japanese


• 環状ペプチドによるHGF阻害と高速原子間力顕微鏡による分子動態計測

  酒井 克也, 佐藤 拓輝, 柴田 幹大, 高木 淳一, 加藤 幸成, 向井 英史, 渡辺 恭良, 矢野 聖二, 管 裕明, 松本 邦夫

  (公社)日本生化学会, Sep. 2019, 日本生化学会大会プログラム・講演要旨集, 92回, [2T09a - 03], Japanese

  [Refereed]


• 活性型HGFの選択的検出によるMET活性化状態の診断(Specific Detection of Active HGF for Diagnosis Reflecting Activation Status of HGF-MET Signaling by Macrocyclic Peptide)

  佐藤 拓輝, 酒井 克也, 今村 龍, 向井 英史, 渡辺 恭良, 矢野 聖二, 松本 邦夫

  (一社)日本癌学会, Sep. 2019, 日本癌学会総会記事, 78回, J - 3012, English


• 活性型HGFの選択的検出によるMET活性化状態の診断(Specific Detection of Active HGF for Diagnosis Reflecting Activation Status of HGF-MET Signaling by Macrocyclic Peptide)

  佐藤 拓輝, 酒井 克也, 今村 龍, 向井 英史, 渡辺 恭良, 矢野 聖二, 松本 邦夫

  日本癌学会, Sep. 2019, 日本癌学会総会記事, 78回, J - 3012, English

  [Refereed]


• Mental fatigue is linked with attentional bias for sad stimuli.

  Kyosuke Watanabe, Akihiro T Sasaki, Kanako Tajima, Kenji Mizuseki, Kei Mizuno, Yasuyoshi Watanabe

  Previous studies have revealed that patients with chronic fatigue syndrome and affective disorders (such as depression and anxiety disorders) exhibit a vigilant attentional bias toward negative emotional stimuli. However, it remains unclear whether the change in an attentional bias for negative emotional stimuli can be induced by mental fatigue in healthy individuals. To address this question, we examined healthy participants' (n = 27) performance in a visual probe task and emotional Stroop task before and after the mental-fatigue-inducing task. We demonstrated that acute mental fatigue induced by the long-lasting working memory task led to the alteration of cognitive processing of negative emotional information in the healthy volunteers.

  Jun. 2019, Scientific reports, 9(1) (1), 8797 - 8797, English, International magazine

  Scientific journal


• Macrocyclic peptide-based inhibition and imaging of hepatocyte growth factor.

  Katsuya Sakai, Toby Passioura, Hiroki Sato, Kenichiro Ito, Hiroki Furuhashi, Masataka Umitsu, Junichi Takagi, Yukinari Kato, Hidefumi Mukai, Shota Warashina, Maki Zouda, Yasuyoshi Watanabe, Seiji Yano, Mikihiro Shibata, Hiroaki Suga, Kunio Matsumoto

  Activation of hepatocyte growth factor (HGF) by proteolytic processing is triggered in cancer microenvironments, and subsequent signaling through the MET receptor is involved in cancer progression. However, the structure of HGF remains elusive, and few small/medium-sized molecules can modulate HGF. Here, we identified HiP-8, a macrocyclic peptide consisting of 12 amino acids, which selectively recognizes active HGF. Biochemical analysis and real-time single-molecule imaging by high-speed atomic force microscopy demonstrated that HiP-8 restricted the dynamic domains of HGF into static closed conformations, resulting in allosteric inhibition. Positron emission tomography using HiP-8 as a radiotracer enabled noninvasive visualization and simultaneous inhibition of HGF-MET activation status in tumors in a mouse model. Our results illustrate the conformational change in proteolytic activation of HGF and its detection and inhibition by a macrocyclic peptide, which may be useful for diagnosis and treatment of cancers.

  Jun. 2019, Nature chemical biology, 15(6) (6), 598 - 606, English, International magazine

  Scientific journal


• 動的PETイメージングとLC/MS/MS解析を組み合わせた核酸医薬リポソーム製剤の動態評価

  向井 英史, 畑中 剣太朗, 八木 信宏, 藁科 翔太, 造田 真希, 高橋 麻衣子, 成島 和哉, 藪内 隼人, 岩野 淳子, 窪山 剛之, 榎園 淳一, 和田 康弘, 渡辺 恭良

  日本DDS学会, Jun. 2019, 日本DDS学会学術集会プログラム予稿集, 35回, 149 - 149, Japanese


• PET imaging of 11C-labeled coenzyme Q10: Comparison of biodistribution between [11C]ubiquinol-10 and [11C]ubiquinone-10.

  Kyosuke Watanabe, Satoshi Nozaki, Miki Goto, Ken-Ichi Kaneko, Emi Hayashinaka, Satsuki Irie, Akira Nishiyama, Kazuaki Kasai, Kenji Fujii, Yasuhiro Wada, Kei Mizuno, Kenji Mizuseki, Hisashi Doi, Yasuyoshi Watanabe

  Coenzyme Q10 (CoQ10) plays a key role not only as an essential electron carrier in the mitochondrial electron transport chain, but also as an antioxidant to protect cells from oxidative stress. CoQ10 supplementation is expected to be effective for a variety of diseases. The predominant forms of CoQ10 are the ubiquinol-10 (reduced form) and ubiquinone-10 (oxidized form). Both forms of CoQ10 supplements are commercially available, however, their kinetic difference is still unclear. In order to conduct in vivo analysis of the kinetics of ubiquinol-10 and ubiquinone-10, we succeeded in synthesizing 11C-labeled ubiquinol-10 ([11C]UQL) and ubiquinone-10 ([11C]UQN), respectively. In the present study, we aimed to investigate the kinetics of [11C]UQL and [11C]UQN, both of which were administered via the tail vein of 8-week-old male Sprague-Dawley rats. Whole-body positron emission tomography (PET) imaging was performed to follow the time course of accumulation in the liver, spleen, brain, and other organs. Then, at the two typical time points at 20 or 90 min after injection, we conducted the biodistribution study. Various organs/tissues and blood were collected, weighed and counted with a gamma counter. Percent injected dose per gram of tissue (%ID/g) was calculated as the indicator of the accumulation of each compound. As the results, at both time points, %ID/g of [11C]UQL in the cerebrum, cerebellum, white adipose tissue, muscle, kidney, and testis were higher (P < 0.05) than that of [11C]UQN: at 90-min time point, %ID/g of [11C]UQL in the brown adipose tissue was higher (P < 0.05) than that of [11C]UQN: on the contrary, %ID/g of [11C]UQL in the spleen was lower (P < 0.05) than that of [11C]UQN at 90 min. In a separate study of the metabolite analysis in the plasma, UQL injected into the tail vein of rats was almost unchanged during the PET scanning time, but UQN was gradually converted to the reduced form UQL. Therefore, the uptake values of UQL into the tissues and organs were rather accurate but those of UQN might be the sum of UQN uptake and partly converted UQL uptake. These studies suggested that the accumulation level of administered CoQ10 differs depending on its redox state, and that CoQ10 redox state could be crucial for optimization of the effective supplementation.

  May 2019, Biochemical and biophysical research communications, 512(3) (3), 611 - 615, English, International magazine

  [Refereed]

  Scientific journal


• Facile radiosyntheses of [C-11]tetrazoles and [C-11]triazines from (hetero)arylborons

  Zhouen Zhang, Takashi Niwa, Yasuyoshi Watanabe, Takamitsu Hosoya

  May 2019, JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS, 62, S243 - S244, English


• Palladium/copper-mediated rapid C-11-cyanation of (hetero)arylstannanes

  Zhouen Zhang, Takashi Niwa, Yasuyoshi Watanabe, Takamitsu Hosoya

  May 2019, JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS, 62, S48 - S49, English


• 非天然型アミノ酸含有抗体発現生産技術と生体直交反応性キレーター修飾の組み合わせによる高均一な64Cu標識トラスツズマブFabの作製

  仁 欽, 藁科 翔太, 毛利 浩太, 高橋 麻衣子, 金山 洋介, 高橋 美穂子, 林 明子, 林中 恵美, 和田 康弘, 渡辺 恭良, 坂本 健作, 向井 英史

  日本分子イメージング学会, May 2019, JSMI Report, 12(2) (2), 98 - 98, Japanese


• [18F]DPA-714を用いたPETイメージングによるてんかんモデルラットにおける神経炎症の定量的評価

  金子 健一, 馬渡 彩, 神母坂 あみ, 入江 さつき, 林中 恵美, 和田 康弘, 土居 久志, 崔 翼龍, 渡辺 恭良

  日本分子イメージング学会, May 2019, JSMI Report, 12(2) (2), 100 - 100, Japanese


• 悪性中皮腫特異的マーカーを標的とした抗体PETイメージング

  田原 強, 辻 祥太郎, 仁 欽, 武 玉萍, 井上 美智子, 林中 恵美, 和田 康弘, 渡辺 恭良, 向井 英史, 今井 浩三, 崔 翼龍

  日本分子イメージング学会, May 2019, JSMI Report, 12(2) (2), 138 - 138, Japanese


• 疲労動物モデルに対する電解水素水の疲労軽減効果研究

  胡 迪, 李 丹溪, 重田 美香, 岡内 隆, 橘 孝士, 樺山 繁, 大崎 雄介, 渡辺 恭良, 崔 翼龍

  日本疲労学会, May 2019, 日本疲労学会誌, 15(1) (1), 64 - 64, Japanese


• Amyloid-Negative Dementia in the Elderly is Associated with High Accumulation of Tau in the Temporal Lobes

  Jun Takeuchi, Takayuki Kikukawa, Haruna Saito, Itsuki Hasegawa, Akitoshi Takeda, Hiroyuki Hatsuta, Joji Kawabe, Yasuhiro Wada, Aya Mawatari, Ami Igesaka, Hisashi Doi, Yasuyoshi Watanabe, Hitoshi Shimada, Soichiro Kitamura, Makoto Higuchi, Tetsuya Suhara, Yoshiaki Itoh

  Background: We previously reported that among cases clinically diagnosed with Alzheimer’s disease, the proportion of amyloid beta (Aβ) -negative case increases in the elderly population. Tauopathy including Argyrophilic Grain Disease (AGD) and Neurofibrillary Tangle-Predominant Dementia (NFTPD), may be the leading causes of such dementia. Objective: To evaluate the involvement of tau, we studied tau accumulation in Amyloid-Negative Dementia Cases in the Elderly (ANDE) with Positron Emission Tomography (PET). Methods: Seven cases with slowly progressive dementia who were older than 80 years and were negative for Aβ were studied. In one case, autopsy obtained 2 years after the PET examination revealed neurofibrillary tangles limited around the parahippocampal gyrus. Four cases showed strong laterality in magnetic resonance imaging atrophy (clinical AGD), while the other three cases had no significant laterality in atrophy (clinical NFTPD). Age-corrected PET data of healthy controls (HC; n = 12) were used as control. Tau accumulation was evaluated with [11C]PBB3-PET. Results: High accumulation was found in the lateral temporal cortex in ANDE. In autopsy case, scattered neurofibrillary tangles were found in the parahippocampal gyrus. In addition, there was a very high accumulation of PBB3 in the large area of bilateral parietal lobes, although no corresponding tau component was found in the autopsied case. Conclusion: Relatively high burden of tau deposition was commonly observed in the lateral temporal cortex and parietal cortex of ANDE, part of which may explain dementia in these subjects. [11C]PBB3 may be useful in detecting tauopathy in ANDE.

  Bentham Science Publishers Ltd., Mar. 2019, The Open Biomedical Engineering Journal, 13(1) (1), 55 - 66, English

  Scientific journal


• Decreased alpha-band oscillatory brain activity prior to movement initiated by perception of fatigue sensation.

  Akira Ishii, Takashi Matsuo, Chika Nakamura, Masato Uji, Takahiro Yoshikawa, Yasuyoshi Watanabe

  Fatigue is a health problem prevalent in modern societies. Fatigue sensation plays an important role as a biological alarm urging rest to maintain homeostasis, and clarifying the neural mechanisms related to fatigue sensations by which we decide to engage in rest is therefore essential. This study enrolled healthy male volunteers and showed that the decrease in alpha-band power as assessed by magnetoencephalography of the left Brodmann's area (BA) 6 before perception of fatigue when a button-press based on the level of fatigue was required was smaller than that before perception of the intention to move when a voluntary button-press was required. In addition, the decrease of alpha-band power in the left BA 6 before the perception of fatigue was not altered compared with that in the right BA 6 when a button-press based on the level of fatigue was required. These results suggest that the button-press based on the perception of fatigue is not prepared before the perception of fatigue. These findings will advance the understanding of the neural mechanisms related to subjective feelings such as fatigue sensation.

  Mar. 2019, Scientific reports, 9(1) (1), 4000 - 4000, English, International magazine

  Scientific journal


• Improved Immuno-PET Imaging of HER2-Positive Tumors in Mice: Urokinase Injection-Triggered Clearance Enhancement of 64Cu-Trastuzumab.

  Qin Ren, Kohta Mohri, Shota Warashina, Yasuhiro Wada, Yasuyoshi Watanabe, Hidefumi Mukai

  Immuno-positron emission tomography (immuno-PET) is expected to improve the specificity of small chemical tracers such as 18F-fluorodeoxyglucose. Whole antibodies significantly accumulate in target molecule-expressing tumors but frequently persist too long in the blood circulation for imaging purposes. We investigated the utility of whole antibodies, 64Cu-labeled via a urokinase-substrate linker, and their exogenous urokinase-responsive cleavage to enhance clearance of immuno-PET probes from the blood and shorten the time required to develop adequate imaging contrast. Specifically, we used 64Cu-labeled trastuzumab in human epidermal growth factor receptor 2 (HER2)-positive tumor-bearing mice. 64Cu-labeled trastuzumab with a urokinase-cleavage site (64Cu-CB-TE1A1P-USL-trastuzumab) was synthesized using a bifunctional chelator incorporating an urokinase substrate peptide. Urokinase cleavage was analyzed in vitro by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and radio-gel permeation-high-performance liquid chromatography. Improvements in radioisotope clearance and HER2-imaging by urokinase injection were evaluated by PET imaging and ex vivo biodistribution studies in A431 tumor-bearing mice. 64Cu-CB-TE1A1P-USL-trastuzumab was cleaved into smaller radioactive fragments by 20 000 IU/mL urokinase treatment in vitro at an efficacy of ∼95%. The probe targeted HER2 in A431 tumors in mice within 24 h post-injection, and approximately two-thirds of the probe in the blood circulation was eliminated via renal clearance of radioactive fragments after three urokinase injections. Therefore, the tumor/blood ratio increased 3.0-fold. Without urokinase injection, the tumor accumulation of 64Cu-CB-TE1A1P-USL-trastuzumab slowly increased, and the blood radioactivity decreased over 72 h. However, the tumor/blood ratios in mice after three urokinase injections were higher at 24 h than those in mice without injections at 72 h. The results indicate that our approach shortened the time required to develop adequate imaging contrast of immuno-PET by >2 days. Therefore, this approach can benefit high-sensitivity imaging under lower radioactive decay conditions and can decrease patient radiation exposure. In addition, it could reduce other adverse effects of radioimmunotherapy.

  Mar. 2019, Molecular pharmaceutics, 16(3) (3), 1065 - 1073, English, International magazine

  Scientific journal


• 211At-labeled immunoconjugate via a one-pot three-component double click strategy: practical access to α-emission cancer radiotherapeutics.

  Katsumasa Fujiki, Yousuke Kanayama, Shinya Yano, Nozomi Sato, Takuya Yokokita, Peni Ahmadi, Yasuyoshi Watanabe, Hiromitsu Haba, Katsunori Tanaka

  α-Emission radiotherapeutics has potential to be one of most effective cancer therapeutics. Herein, we report a facile synthesis of an 211At-labeled immunoconjugate for use as an α-emission molecular targeting therapy. We synthesized a tetrazine probe modified with closo-decaborate(2-), a prosthetic group that forms a bioavailable stable complex with 211At. Our one-pot three-component double-click labeling method was used to attach decaborate to trastuzumab (anti-HER2 antibody) using decaborate-tetrazine and TCO-aldehyde probes without reducing the antibody binding affinity. Labeling the decaborate-attached trastuzumab with 211At produced in the cyclotron at the RIKEN Nishina Center, at which highly radioactive 211At can be produced, readily furnished the 211At-labeled trastuzumab with a maximum specific activity of 15 MBq μg-1 and retention of the native binding affinity. Intratumor injection of the 211At-labeled trastuzumab in BALB/c nude mice implanted with HER2-expressing epidermoid cancer cells yielded efficient accumulation at the targeted tumor site as well as effective suppression of tumor growth.

  Feb. 2019, Chemical science, 10(7) (7), 1936 - 1944, English, International magazine

  Scientific journal


• Cover Image, Volume 62, Issue 2

  Miki Goto, Akira Nishiyama, Takao Yamaguchi, Kyosuke Watanabe, Kenji Fujii, Yasuyoshi Watanabe, Hisashi Doi

  Wiley, Feb. 2019, Journal of Labelled Compounds and Radiopharmaceuticals, 62(2) (2), i - i, English

  Scientific journal


• Synthesis of 11 C-labeled ubiquinone and ubiquinol via Pd0 -mediated rapid C-[11 C]methylation using [11 C]methyl iodide and 39-demethyl-39-(pinacolboryl)ubiquinone.

  Miki Goto, Akira Nishiyama, Takao Yamaguchi, Kyosuke Watanabe, Kenji Fujii, Yasuyoshi Watanabe, Hisashi Doi

  To enable positron emission tomography (PET) imaging of the in vivo kinetics of ubiquinone and ubiquinol, which is referred to as coenzyme Q10 , their 11 C-radiolabeled counterparts were synthesized herein. 11 C-Labeled ubiquinone [11 C]-1 was realized by Pd-mediated rapid C-[11 C]methylation of [11 C]CH3 I with 39-demethyl-39-(pinacolboryl)ubiquinone, prepared by Ru-catalyzed olefin metathesis of unradiolabeled ubiquinone with 2-(pinacolboryl)propene. Subsequent reduction of [11 C]-1 using Na2 S2 O4 yielded 11 C-labeled ubiquinol [11 C]-2. The synthesis time and [11 C]CH3 I-based radiochemical yield of [11 C]-1 were within 36 minutes and up to 53%, while those of [11 C]-2 were within 38 minutes and up to 39%, respectively. After radiopharmaceutical formulation, the qualities of [11 C]-1 and [11 C]-2 were confirmed to be applicable for animal PET studies. The analytical values of [11 C]-1 and [11 C]-2 are as follows: radioactivity of up to 3.5 and 1.4 GBq, molar activity of 21 to 78 and 48 to 76 GBq/μmol, radiochemical purity of greater than 99% and greater than 95%, and chemical purity of greater than 99% and 77%, respectively. The concept behind this radiolabeling procedure is that unradiolabeled natural ubiquinone can be converted to 11 C-radiolabeled ubiquinone and ubiquinol via a pinacolborane-substituted ubiquinone derivative. Each PET probe was used for molecular imaging using rats to investigate the in vivo kinetics and biodistribution of the coenzyme Q10 .

  Feb. 2019, Journal of labelled compounds & radiopharmaceuticals, 62(2) (2), 86 - 94, English, International magazine

  Scientific journal


• Pharmacokinetic evaluation of liposomal nanoparticle-encapsulated nucleic acid drug: A combined study of dynamic PET imaging and LC/MS/MS analysis.

  Hidefumi Mukai, Kentaro Hatanaka, Nobuhiro Yagi, Shota Warashina, Maki Zouda, Maiko Takahashi, Kazuya Narushima, Hayato Yabuuchi, Junko Iwano, Takeshi Kuboyama, Junichi Enokizono, Yasuhiro Wada, Yasuyoshi Watanabe

  In vivo biodistribution analyses, especially in tumors, of nucleic acids delivered with nanoparticles are important to develop drug delivery technologies for medical use. We previously developed wrapsome® (WS), an ~100 nm liposomal nanoparticle that can encapsulate siRNA, and reported that WS accumulates in tumors in vivo and inhibits their growth by an enhanced permeability and retention effect. In the present study, we evaluated the pharmacokinetics of nucleic acid-containing nanoparticles by combining dynamic positron emission tomography (PET) imaging and liquid chromatography-tandem mass spectrometry (LC/MS/MS) analysis. An 18-mer phosphorothioate oligodeoxynucleotide (ODN), trabedersen, was used as a model drug and was encapsulated in WS. Dynamic PET imaging and time-activity curve analysis of WS-encapsulated 64Cu-labeled ODNs administered to mice with MIA PaCa-2 subcutaneous xenograft tumors showed tumor accumulation (~3% injected dose per gram (%ID/g)) and liver accumulation (~30 %ID/g) at 24 h. Under these conditions, LC/MS/MS analysis showed that the level of intact ODNs was 1.62 %ID/g in the tumor and 1.70 %ID/g in the liver. From these pharmacokinetic data, the intact/accumulated ODN ratios were calculated using the following equation: intact/accumulated ODN ratio (%) = %ID/g LC/MS/MS, tissue, mean/%ID/g PET, tissue, mean × 100. Interestingly, the ratios for the tumor and kidney were maintained at 20-50% over 48 h after administration of the WS-encapsulated form. In contrast, the ratio for the liver rapidly decreased at 24 h, showing the same pattern as that for naked ODN. These different patterns indicate that WS effectively protected the ODN in the tumor and kidney, but protected it less efficiently in the liver. A combined approach of dynamic PET imaging and LC/MS/MS analysis will assist the development of nanoparticle-encapsulated nucleic acid drugs, such as those using WSs, to determine their detailed pharmacokinetics.

  Jan. 2019, Journal of controlled release : official journal of the Controlled Release Society, 294, 185 - 194, English, International magazine

  Scientific journal


• [11C]PBB3-PETを用いた神経原線維変化優位型認知症の脳内タウ蓄積分布に関する検討

  竹内 潤, 齊藤 明奈, 武田 景敏, 河邉 讓治, 和田 康弘, 馬渡 彩, 土居 久志, 渡辺 恭良, 北村 聡一郎, 島田 斉, 樋口 真人, 須原 哲也, 伊藤 義彰

  (一社)日本神経学会, Dec. 2018, 臨床神経学, 58(Suppl.) (Suppl.), S312 - S312, Japanese


• PET Imaging Analysis of Vitamin B1 Kinetics with [11C]Thiamine and its Derivative [11C]Thiamine Tetrahydrofurfuryl Disulfide in Rats.

  Satoshi Nozaki, Aya Mawatari, Yuka Nakatani, Emi Hayashinaka, Yasuhiro Wada, Yukihiro Nomura, Takahito Kitayoshi, Kouji Akimoto, Shinji Ninomiya, Hisashi Doi, Yasuyoshi Watanabe

  PURPOSE: Thiamine is an essential component of glucose metabolism and energy production. The disulfide derivative, thiamine tetrahydrofurfuryl disulfide (TTFD), is better absorbed than readily-available water-soluble thiamine salts because it does not require the rate-limiting transport system required for thiamine absorption. However, the detailed pharmacokinetics of thiamine and TTFD under normal and pathological conditions have not yet been clarified. C-11-labeled thiamine and TTFD were recently synthesized by our group. In this study, to clarify the differences in pharmacokinetics and metabolism of these probes, a quantitative PET imaging study and radiometabolite analysis of C-11-labeled thiamine and TTFD were performed in the rat heart. PROCEDURES: Positron emission tomography (PET) imaging with [11C]thiamine and [11C]TTFD was performed in normal rats to determine the pharmacokinetics of these probes, and the radiometabolites of both probes from the blood and heart tissue were analyzed by thin-layer chromatography. RESULTS: Accumulation of [11C]TTFD was significantly higher than that of [11C]thiamine in the rat heart. Moreover, as a result of the radiometabolite analysis of heart tissue at 15 min after the injection of [11C]TTFD, thiamine pyrophosphate, which serves as a cofactor for the enzymes involved in glucose metabolism, was found as the major radiometabolite and at a significantly higher level than in the [11C]thiamine-injected group. CONCLUSIONS: PET imaging techniques for visualizing the kinetics and metabolism of thiamine using [11C]thiamine and [11C]TTFD were developed in this study. Consequently, noninvasive PET imaging for the pathophysiology of thiamine-related cardiac function may provide novel information about heart failure and related disorders.

  Dec. 2018, Molecular imaging and biology, 20(6) (6), 1001 - 1007, English, International magazine

  Scientific journal


• Association between aromatase in human brains and personality traits.

  Kayo Takahashi, Takamitsu Hosoya, Kayo Onoe, Tadayuki Takashima, Masaaki Tanaka, Akira Ishii, Yasuhito Nakatomi, Shusaku Tazawa, Kazuhiro Takahashi, Hisashi Doi, Yasuhiro Wada, Yasuyoshi Watanabe

  Aromatase, an enzyme that converts androgens to estrogens, has been reported to be involved in several brain functions, including synaptic plasticity, neurogenesis, neuroprotection, and regulation of sexual and emotional behaviours in rodents, pathophysiology of Alzheimer's disease and autism spectrum disorders in humans. Aromatase has been reported to be involved in aggressive behaviours in genetically modified mice and in personality traits by genotyping studies on humans. However, no study has investigated the relationship between aromatase in living brains and personality traits including aggression. We performed a positron emission tomography (PET) study in 21 healthy subjects using 11C-cetrozole, which has high selectivity and affinity for aromatase. Before performing PET scans, subjects answered the Buss-Perry Aggression Questionnaire and Temperament and Character Inventory to measure their aggression and personality traits, respectively. A strong accumulation of 11C-cetrozole was detected in the thalamus, hypothalamus, amygdala, and medulla. Females showed associations between aromatase levels in subcortical regions, such as the amygdala and supraoptic nucleus of the hypothalamus, and personality traits such as aggression, novelty seeking, and self-transcendence. In contrast, males exhibited associations between aromatase levels in the cortices and harm avoidance, persistence, and self-transcendence. The association of aromatase levels in the thalamus with cooperativeness was common to both sexes. The present study suggests that there might exist associations between aromatase in the brain and personality traits. Some of these associations may differ between sexes, while others are likely common to both.

  Nov. 2018, Scientific reports, 8(1) (1), 16841 - 16841, English, International magazine

  Scientific journal


• Palladium(ii)-mediated rapid 11C-cyanation of (hetero)arylborons.

  Zhouen Zhang, Takashi Niwa, Yasuyoshi Watanabe, Takamitsu Hosoya

  Nov. 2018, Organic & biomolecular chemistry, 16(41) (41), 7711 - 7716, English, International magazine

  Scientific journal


• Disulfiram enhanced delivery of orally administered copper into the central nervous system in Menkes disease mouse model.

  Takao Hoshina, Satoshi Nozaki, Takashi Hamazaki, Satoshi Kudo, Yuka Nakatani, Hiroko Kodama, Haruo Shintaku, Yasuyoshi Watanabe

  INTRODUCTION: Menkes disease (MD) is an X-linked recessive disorder caused by dysfunction of a copper-transporting protein, leading to severe neurodegeneration in early childhood. We investigated whether a lipophilic copper chelator, disulfiram, could enhance copper absorption from the intestine and transport copper across the blood-brain barrier in MD model mice. METHODS: Wild type and MD model mice were pretreated with disulfiram for 30 min before oral administration of 64CuCl2. Each organ was sequentially analyzed for radioactivity with γ counting. Copper uptake into the brain parenchyma was assessed by ex vivo autoradiography. RESULTS: In wild type mice, orally administered copper was initially detected in the intestine within 2 h, reaching a maximum level in the liver (19.6 ± 3.8 percentage injected dose per gram [%ID/g]) at 6 h. In MD model mice, the copper reached the maximum level in the liver (5.3 ± 1.5 %ID/g) at 4 h, which was lower than that of wild type mice (19.0 ± 7.4 %ID/g) (P < 0.05). Pretreatment of disulfiram in MD model mice increased the copper level in the brain (0.59 ± 0.28 %ID/g) at 24 h compared with MD model mice without disulfiram (0.07 ± 0.05 %ID/g) (P < 0.05). Ex vivo autoradiography revealed that high levels of copper uptake was observed in the cerebral cortex upon disulfiram pretreatment. CONCLUSION: Our data demonstrated that disulfiram enhanced the delivery of orally administered copper into the central nervous system in MD model mice. The administration of disulfiram will enable patients to avoid unpleasant subcutaneous copper injection in the future.

  Nov. 2018, Journal of inherited metabolic disease, 41(6) (6), 1285 - 1291, English, International magazine

  Scientific journal


• [Brain Science on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome].

  Yasuyoshi Watanabe

  Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease characterized by chronic, profound, disabling, and unexplained fatigue. A variety of studies have been performed to establish objective biomarkers of the disease, including positron emission tomography (PET) molecular imaging and neuro-functional imaging using magnetic resonance imaging (MRI) and magnetoencephalogram (MEG). In this chapter, we summarize the results from PET, MRI, and MEG imaging. Regional cerebral blood flow and glucose utilization rates are decreased in patients with ME/CFS as compared with age- and sex-matched healthy subjects. Acetyl-L-carnitine uptake into the releasable pool of glutamate and serotonin transporters densities are decreased in a few specific brain regions, mostly in the anterior cingulate in the patients. Although it is hypothesized that brain inflammation is involved in the pathophysiology of ME/CFS, there was no direct evidence of neuroinflammation in patients. Our recent PET study successfully demonstrated that neuroinflammation is present in widespread brain areas in ME/CFS patients, and is associated with the severity of neuropsychological symptoms. Evaluation of neuroinflammation in patients with ME/CFS may be essential for understanding the core pathophysiology, as well as for developing objective diagnostic criteria and effective medical treatments for ME/CFS. By using specific neurological features of these patients such as prefrontal cortical atrophies and the over-guarding phenomenon were found using MRI and functional MRI, respectively. We here describe related pathophysiological findings and topics in order to aid in the development of future therapies for ME/CFS patients.

  Nov. 2018, Brain and nerve = Shinkei kenkyu no shinpo, 70(11) (11), 1193 - 1201, Japanese, Domestic magazine

  Scientific journal


• Expanding the Applicability of the Metal Labeling of Biomolecules by the RIKEN Click Reaction: A Case Study with Gallium-68 Positron Emission Tomography.

  Yuka Nakamoto, Ambara R Pradipta, Hidefumi Mukai, Maki Zouda, Yasuyoshi Watanabe, Almira Kurbangalieva, Peni Ahmadi, Yoshiyuki Manabe, Koichi Fukase, Katsunori Tanaka

  Radiolabeled biomolecules with short half-life times are of increasing importance for positron emission tomography (PET) imaging studies. Herein, we demonstrate an improved and generalized method for synthesizing a [radiometal]-unsaturated aldehyde as a lysine-labeling probe that can be easily conjugated into various biomolecules through the RIKEN click reaction. As a case study, 68 Ga-PET imaging of U87MG xenografted mice is demonstrated by using the 68 Ga-DOTA-RGDyK peptide, which is selective to αV β3 integrins.

  Oct. 2018, Chembiochem : a European journal of chemical biology, 19(19) (19), 2055 - 2060, English, International magazine

  Scientific journal


• Logopenic型進行性失語症患者における臨床症状とアミロイド・タウPETとの関連

  武田 景敏, 竹内 潤, 齊藤 明奈, 河邉 譲治, 和田 康弘, 馬渡 彩, 神母坂 あみ, 土居 久志, 渡辺 恭良, 北村 聡一郎, 島田 斉, 樋口 真人, 須原 哲也, 伊藤 義彰

  (一社)日本認知症学会, Sep. 2018, Dementia Japan, 32(3) (3), 419 - 419, Japanese


• Amyloid deposition and CBF patterns predict conversion of mild cognitive impairment to dementia.

  Takayuki Kikukawa, Takato Abe, Suzuka Ataka, Haruna Saito, Itsuki Hasegawa, Toshikazu Mino, Jun Takeuchi, Joji Kawabe, Yasuhiro Wada, Yasuyoshi Watanabe, Yoshiaki Itoh

  Mild cognitive impairment (MCI) can include the transition from a normal state to dementia. To explore biomarkers for the development of dementia, we performed an 18-month follow-up study in 28 patients with amnestic MCI. Amyloid deposition was examined using PiB PET, and cerebral blood flow (CBF) was examined using SPECT. Cognitive function was periodically assessed. The rate of conversion to dementia was higher in the PiB-positive/equivocal group (74%) than in the PiB-negative group (33%) (p = 0.041). Perfusion SPECT was performed in 16 patients. MCI patients with an AD-characteristic pattern of reduced CBF had a higher PiB-positive/equivocal rate (82%) than those with a non-AD pattern (20%) (p = 0.018), and patients with an AD pattern had a higher conversion rate (82%) than those with a non-AD pattern (40%) (p = 0.094). Clinically, all PiB-positive converters were diagnosed as having Alzheimer's disease (AD), whereas PiB-negative converters were thought to have some form of dementia other than AD. Amyloid PET is useful for predicting conversion to AD in MCI patients. A pattern analysis of perfusion SPECT findings might also be helpful for predicting conversion to AD, but with a lower specificity.

  Sep. 2018, Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 39(9) (9), 1597 - 1602, English, International magazine

  Scientific journal


• A voxel-based analysis of neurobiological mechanisms in placebo analgesia in rats.

  Ying Zeng, Di Hu, Wei Yang, Emi Hayashinaka, Yasuhiro Wada, Yasuyoshi Watanabe, Qunli Zeng, Yilong Cui

  Sep. 2018, NeuroImage, 178, 602 - 612, English, International magazine

  [Refereed]

  Scientific journal


• A viable strategy for screening the effects of glycan heterogeneity on target organ adhesion and biodistribution in live mice.

  Akihiro Ogura, Sayaka Urano, Tsuyoshi Tahara, Satoshi Nozaki, Regina Sibgatullina, Kenward Vong, Takehiro Suzuki, Naoshi Dohmae, Almira Kurbangalieva, Yasuyoshi Watanabe, Katsunori Tanaka

  This work represents the first broad study of testing diverse heterogenous glycoconjugates (7 different glycoalbumins) for their differential in vivo binding (11 different cancer cell types) in both cell- and animal-based studies. As a result, various changes in biodistribution, excretion, and even tumor adhesion were observed.

  Aug. 2018, Chemical communications (Cambridge, England), 54(63) (63), 8693 - 8696, English, International magazine

  Scientific journal


• Urokinase injection-triggered clearance enhancement of a 4-arm PEG-conjugated 64Cu-bombesin analog tetramer: A novel approach for the improvement of PET imaging contrast.

  Kazushi Matsumura, Maki Zouda, Yasuhiro Wada, Fumiyoshi Yamashita, Mitsuru Hashida, Yasuyoshi Watanabe, Hidefumi Mukai

  Radiolabeled antibodies, polyethylene glycol-conjugated (PEGylated) peptides, liposomes, and other materials were investigated as positron-emission tomography (PET) probes. These substances accumulate in tumors but often remain too long in circulation. We investigated the combination of intravenous urokinase injection and its substrate linker as a triggered radioisotope clearance enhancement system to improve imaging contrast. To this end, we synthesized a four-arm PEGylated 64Cu-bombesin analog tetramer with a urokinase substrate linker. In mouse blood, it was almost perfectly cleaved and degraded into smaller radioactive fragments in vitro with urokinase (≥20,000 IU/mL). In mouse blood circulation, ∼50-65% of the probe was rapidly degraded after the urokinase injection and the radioactive fragments were eliminated mainly from the kidney. In contrast, tumor radioactivity levels did not change, and therefore, the tumors were clearly visualized. The tumor/blood ratio, an indicator of imaging contrast, increased 2.5 times, while elimination of the radioisotope from the blood was enhanced. This approach has the potential to improve imaging contrast using various PET probes. It could also shorten the time required to obtain sufficient contrast and decrease patient radiation exposure.

  Jul. 2018, International journal of pharmaceutics, 545(1-2) (1-2), 206 - 214, English, International magazine

  Scientific journal


• 【in vivoイメージングとセラノスティクスの新展開】PETを用いた薬物動態解析とDDS研究開発

  向井 英史, 渡辺 恭良

  日本DDS学会, Jul. 2018, Drug Delivery System, 33(3) (3), 204 - 213, Japanese

  [Refereed]

  Scientific journal


• The neural effects of positively and negatively re-experiencing mental fatigue sensation: a magnetoencephalography study.

  Akira Ishii, Takuya Ishizuka, Yuki Muta, Masaaki Tanaka, Emi Yamano, Yasuyoshi Watanabe

  Fatigue sensation is an essential biological alarm that urges us to take rest to avoid disrupting homeostasis and thus plays an important role in maintaining well-being. However, there are situations in which the anticipation of unpleasant fatigue sensation undesirably reduces motivation for activity. The aim of this study was to examine whether thinking positively about the fatigue sensation would increase motivation to accomplish the workload. Fourteen healthy male volunteers participated in this study and performed a two-back test for 30 min to induce mental fatigue sensation. After their subjective level of fatigue had recovered to the baseline level, they re-experienced the fatigue sensation experienced in the two-back test positively, negatively, and without any modification (i.e., re-experienced the fatigue sensation as it was). The level of motivation to perform another two-back test they felt during the re-experiencing was assessed. The neural activity related to the re-experiencing was recorded using magnetoencephalography. The level of the motivation to perform another two-back test was increased by positively re-experiencing the fatigue sensation. The increase in delta band power in Brodmann area 7 was positively associated with the increase in motivation. These results show that positive thinking about fatigue sensation can enhance motivation and suggest that this enhanced motivation may have some effects on visual attention system.

  Jun. 2018, Experimental brain research, 236(6) (6), 1735 - 1747, English, International magazine

  Scientific journal


• Kamikihito improves cancer-related fatigue by restoring balance between the sympathetic and parasympathetic nervous systems.

  Satoshi Tamada, Kyoko Ebisu, Sayaka Yasuda, Minoru Kato, Noriko Ninomiya, Takeshi Yamasaki, Taro Iguchi, Tatsuya Nakatani, Yasuyoshi Watanabe

  BACKGROUND: Cancer-related fatigue is one of the most prevalent symptoms that patients with cancer experience, but the mechanisms underlying it are unknown. We aimed to quantify and mechanistically evaluate the improvement in fatigue related to administration of the Kampo medicine, Kamikihito. MATERIALS AND METHODS: Initially, we recruited outpatients with urological diseases and compared fatigue levels of 37 patients with cancer with a control group of 23 volunteers who had recovered completely from cancer or who were being treated for dysuria. Fatigue level was estimated using an autonomic function analyzer. Then, Kamikihito was administered to another 35 patients treated with hormone or antitumor therapy for prostate cancer and metastatic renal cell cancer. Subjective fatigue and other problems of the patients were assessed using the Chalder fatigue scale, the Center for Epidemiologic Studies Depression scale, and the Epworth sleepiness scale. Serum levels of derivatives of reactive oxygen species and biological antioxidant potential were also measured. RESULTS: Patients in the cancer treatment group experienced more fatigue compared with the control patients when evaluated using an autonomic function analyzer. The group of 35 patients who were administered Kamikihito showed improved scores for fatigue, depression, and sleepiness. Autonomic nervous system balance was also improved with Kamikihito administration. The Kamikihito group also had significantly lower reactive oxygen species metabolite levels and significantly higher antioxidant potential. CONCLUSIONS: Fatigue was more serious in patients with cancer than in control patients. Kamikihito rescued this fatigue and improved anxiety and sleepiness. It restored autonomic nervous system balance and antioxidant function.

  Jun. 2018, Prostate international, 6(2) (2), 55 - 60, English, International magazine

  Scientific journal


• Quantification of receptor activation by oxytocin and vasopressin in endocytosis-coupled bioluminescence reduction assay using nanoKAZ.

  Isao Kii, Shino Hirahara-Owada, Masataka Yamaguchi, Takashi Niwa, Yuka Koike, Rie Sonamoto, Harumi Ito, Kayo Takahashi, Chihiro Yokoyama, Takuya Hayashi, Takamitsu Hosoya, Yasuyoshi Watanabe

  Oxytocin (OXT) and arginine vasopressin (AVP) are structurally similar neuropeptide hormones that function as neurotransmitters in the brain, and have opposite key roles in social behaviors. These peptides bind to their G protein-coupled receptors (OXTR and AVPRs), inducing calcium ion-dependent signaling pathways and endocytosis of these receptors. Because selective agonists and antagonists for these receptors have been developed as therapeutic and diagnostic agents for diseases such as psychiatric disorders, facile methods are in demand for the evaluation of selectivity between these receptors. In this study, we developed a quantitative assay for OXT- and AVP-induced endocytosis of their receptors. The mutated Oplophorus luciferase, nanoKAZ, was fused to OXTR and AVPRs to enable rapid quantification of agonist-induced endocytosis by bioluminescence reduction. Agonist stimulation significantly decreases bioluminescence of nanoKAZ-fused receptors in living cells. Using this system, we evaluated clinically used OXTR antagonist atosiban and a reported pyrazinyltriazole derivative, hereby designated as PF13. Atosiban acted as an antagonist of AVPR1a, as well as an agonist for AVPR1b, whereas PF13 antagonized OXTR more selectively than atosiban, as reported previously. This paper shows a strategy for quantification of agonist-induced endocytosis of OXTR and AVPRs, and confirms its potent utility in the evaluation of agonists and antagonists.

  May 2018, Analytical biochemistry, 549, 174 - 183, English, International magazine

  Scientific journal


• Potential usefulness of Brevibacillus for bacterial cancer therapy: intratumoral provision of tumor necrosis factor-α and anticancer effects.

  Hidefumi Mukai, Maiko Takahashi, Yasuyoshi Watanabe

  Bacterial cancer therapy, wherein bacteria are used as a gene expression system for the exogenous protein of interest in the body, has started becoming a focus area of research; therefore, studying potential bacterial species for use is extremely important. Here, we investigated the use of Brevibacillus choshinensis as an effective and safe provider of anticancer proteins in the body, using a transformant expressing murine tumor necrosis factor-α (mTNF-α). The transformant sustainably provided mTNF-α in tumors in mice for a few hours post-injection. The growth of TNF-α-sensitive tumors was inhibited even by the control transformant, which did not provide mTNF-α; intratumoral mTNF-α provision by Brevibacillus choshinensis had additive effects on tumor growth inhibition. In contrast, intratumorally injected recombinant mTNF-α did not inhibit tumor growth because of rapid elimination from the tumor. Blood biochemical and histochemical analyses showed that intravenous injection of the transformant that did not provide mTNF-α did not lead to tissue injury and dysfunction or infiltration of inflammatory cells over 1 week. Considering the findings, this approach is expected to have a high degree of usability as a delivery system for protein pharmaceuticals, especially from the viewpoints of loading capacity and cost effectiveness.

  May 2018, Cancer gene therapy, 25(3-4) (3-4), 47 - 57, English, International magazine

  Scientific journal


• A Clinical Quantitative Evaluation of Hepatobiliary Transport of [11C]Dehydropravastatin in Humans Using Positron Emission Tomography.

  Ken-Ichi Kaneko, Masaaki Tanaka, Akira Ishii, Yumiko Katayama, Takayoshi Nakaoka, Satsuki Irie, Hideki Kawahata, Takashi Yamanaga, Yasuhiro Wada, Takeshi Miyake, Kota Toshimoto, Kazuya Maeda, Yilong Cui, Masaru Enomoto, Etsushi Kawamura, Norifumi Kawada, Joji Kawabe, Susumu Shiomi, Hiroyuki Kusuhara, Yuichi Sugiyama, Yasuyoshi Watanabe

  Various positron emission tomography (PET) probes have been developed to assess in vivo activities in humans of drug transporters, which aid in the prediction of pharmacokinetic properties of drugs and the impact of drug-drug interactions. We developed a new PET probe, sodium (3R, 5R)-3, 5-dihydroxy-7-((1S, 2S, 6S, 8S)-6-hydroxy-2-methyl-8- ((1-[11C]-(E)-2-methyl-but-2-enoyl) oxy) -1, 2, 6, 7, 8, 8a-hexahydronaphthalen-1-yl) heptanoate ([11C]DPV), and demonstrated its usefulness for the quantitative investigation of Oatps (gene symbol SLCO) and Mrp2 (gene symbol ABCC2) in rats. To further analyze the species differences and verify the pharmacokinetic parameters in humans, serial PET scanning of the abdominal region with [11C]DPV was performed in six healthy volunteers with and without an OATP1Bs and MRP2 inhibitor, rifampicin (600 mg, oral), in a crossover fashion. After intravenous injection, [11C]DPV rapidly distributed to the liver and kidney followed by secretion into the bile and urine. Rifampicin significantly reduced the liver distribution of [11C]DPV 3-fold, resulting in a 7.5-fold reduced amount of excretion into the bile and the delayed elimination of [11C]DPV from the blood circulation. The hepatic uptake clearance (CLuptake, liver) and canalicular efflux clearance (CLint, bile) of [11C]DPV (544 ± 204 and 10.2 ± 3.5 µl/min per gram liver, respectively) in humans were lower than the previously reported corresponding parameters in rats (1800 and 298 µl/min per gram liver, respectively) (Shingaki et al., 2013). Furthermore, rifampicin treatment significantly reduced CLuptake, liver and CLint, bile by 58% and 44%, respectively. These results suggest that PET imaging with [11C]DPV is an effective tool for quantitatively characterizing the OATP1Bs and MRP2 functions in the human hepatobiliary transport system.

  May 2018, Drug metabolism and disposition: the biological fate of chemicals, 46(5) (5), 719 - 728, English, International magazine

  Scientific journal


• がん組織イメージングコントラストの改善を目的としたウロキナーゼ薬剤に対する基質ペプチドを有する免疫PETプローブの有用性評価

  毛利 浩太, 仁 欽, 藁科 翔太, 林中 恵美, 和田 康弘, 渡辺 恭良, 向井 英史

  日本分子イメージング学会, May 2018, JSMI Report, 11(2) (2), 66 - 66, Japanese


• 静脈内投与後腫瘍組織に生着した大腸菌のプラスミド維持の評価

  野村 祥子, Erike Sukowati, 高橋 麻衣子, 渡辺 恭良, 向井 英史

  日本DDS学会, May 2018, 日本DDS学会学術集会プログラム予稿集, 34回, 184 - 184, Japanese


• [18F]Fluorine-incorporated(S)-ketoprofen methyl ester PETイメージングによる神経炎症の定量的評価

  金子 健一, 馬渡 彩, 入江 さつき, 林中 恵美, 和田 康弘, 土居 久志, 崔 翼龍, 渡辺 恭良

  日本分子イメージング学会, May 2018, JSMI Report, 11(2) (2), 124 - 124, Japanese


• 慢性疲労動物を用いた疲労の慢性化機序の解析

  胡 迪, 李 丹渓, 重田 美香, 岡内 隆, 渡辺 恭良, 崔 翼龍

  日本疲労学会, May 2018, 日本疲労学会誌, 14(1) (1), 41 - 41, Japanese


• 慢性疲労に誘発されたラットの体温調節系の機能的変化(Chronic fatigue induced functional change of the thermoregulatory system in rats)

  李 丹渓, 胡 迪, 重田 美香, 岡内 隆, 渡辺 恭良, 崔 翼龍

  日本疲労学会, May 2018, 日本疲労学会誌, 14(1) (1), 64 - 64, English


• ウロキナーゼ静脈内投与により腎クリアランスが促進されコントラストが向上する免疫PETプローブの開発

  仁 欽, 毛利 浩太, 藁科 翔太, 林中 恵美, 和田 康弘, 渡辺 恭良, 向井 英史

  (公社)日本薬学会, Mar. 2018, 日本薬学会年会要旨集, 138年会(2) (2), 244 - 244, Japanese


• [History of Researches on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome].

  Yasuyoshi Watanabe, Hirohiko Kuratsune

  Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease characterized by chronic, profound, disabling, and unexplained fatigue. The first patient with ME/CFS in Japan was identified and described in 1990 by Prof. Teruo Kitani and Dr. Hirohiko Kuratsune of the Research Institute for Microbial Diseases, Osaka University. Since then, a variety of studies have been performed to determine the objective biomarkers of the disease. Although it is hypothesized that brain inflammation is involved in the pathophysiology of ME/CFS, there is to date no direct evidence of neuroinflammation in patients with ME/CFS. Our recent positron emission tomography study successfully demonstrated that microglial activation, which is linked to neuroinflammation, occurs in widespread brain areas in patients with ME/CFS, and is associated with the severity of the neuropsychological symptoms. Thus, evaluation of neuroinflammation in patients with ME/CFS may be essential for understanding the core pathophysiology of the disease, and for developing objective diagnostic criteria and effective medical treatments for ME/CFS. Here, we describe disease-related pathophysiological findings and topics, and discuss the history of the diagnostic and therapeutic attempts based on previous findings in Japan.

  Jan. 2018, Brain and nerve = Shinkei kenkyu no shinpo, 70(1) (1), 5 - 9, Japanese, Domestic magazine

  Scientific journal


• [Neuroinflammation in the Brain of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome].

  Yasuhito Nakatomi, Hirohiko Kuratsune, Yasuyoshi Watanabe

  Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by chronic, profound, disabling, and unexplained fatigue; cognitive impairment; and chronic widespread pain. By using positron emission tomography, our study demonstrated neuroinflammation in the brain of patients with ME/CFS. Neuroinflammation was found to be widespread in the brain areas of the patients with ME/CFS and was associated with the severity of their neuropsychological symptoms. The ongoing research would lead to the establishment of objective diagnostic criteria and development of an appropriate therapy.

  Jan. 2018, Brain and nerve = Shinkei kenkyu no shinpo, 70(1) (1), 19 - 25, Japanese, Domestic magazine

  Scientific journal


• Involvement of the olfactory system in the induction of anti-fatigue effects by odorants.

  Naoko Saito, Emi Yamano, Akira Ishii, Masaaki Tanaka, Junji Nakamura, Yasuyoshi Watanabe

  Some components of the neural circuits underlying innate odor-evoked responses have recently been elucidated. Odor information detected by the olfactory receptors is transmitted from the olfactory bulb to the cortical amygdala, where physiological and emotional states such as attraction or avoidance are controlled. Thus, activation of specific olfactory receptors can elicit changes in physiological and/or psychological state. Here, we examined on the odorant Hex-Hex Mix, which has been reported to induce anti-fatigue effects. Fatigue is a prevalent condition that is often related to overwork and psychological stress. Various anti-fatigue treatments have been developed, including supplements and odorants. However, the mechanisms underlying the anti-fatigue effects of these substances are currently unclear. In the present study, we analyzed the involvement of the olfactory system in the mechanisms underlying this effect. We identified the human olfactory receptors activated by Hex-Hex Mix, and evaluated whether activation of these olfactory receptors by a newly developed odorant elicited a similar anti-fatigue effect to Hex-Hex Mix. We assessed anti-fatigue effects with behavioral tests, and 17 healthy males performed the 2-back test as a fatigue-inducing task with or without exposure to the new odorant. Immediately before and after the task, participants performed a cognitive task to evaluate their level of mental fatigue. We found that the difference value of the correct response rate on the cognitive task in the evaluation session was significantly different between in the odorant condition and in the without-odorant condition during the fatigue-inducing session suggesting that the new odorant may improve performance in the fatigue-inducing condition. The results indicated that the new odorant activates the same olfactory receptors as Hex-Hex Mix, which has been reported to induce anti-fatigue effects. Our findings suggest that the olfactory receptors in the olfactory system may be involved in the attenuation of fatigue.

  2018, PloS one, 13(3) (3), e0195263, English, International magazine

  Scientific journal


• Association of Fatigue and Stress With Gray Matter Volume.

  Keisuke Kokubun, Kiyotaka Nemoto, Hiroki Oka, Hiroki Fukuda, Yoshinori Yamakawa, Yasuyoshi Watanabe

  Stress is associated with a greater risk for various health problems including reduced gray matter volume (GMV) and density in a number of brain regions. Previous studies show that neuroimaging could be a means to objectively evaluate stress. However, to date, no definite neuroimaging-derived measures are available to detect stress. In this research we used the gray-matter brain healthcare quotient (GM-BHQ), an MRI-based quotient for monitoring brain health based on GMV, as an objective scale to measure the association of stress with the whole brain. We recruited 63 healthy adults to acquire structural T1-weighted images and stress levels evaluated using three representative stress scales: the Profile of Mood States (POMS), Perceived Stress Scale (PSS) and Chalder Fatigue Scale (CFS). We found that the GM-BHQ was sensitive to fatigue and the interaction between fatigue and stress.

  2018, Frontiers in behavioral neuroscience, 12, 154 - 154, English, International magazine

  Scientific journal


• Hydrogen-rich water for improvements of mood, anxiety, and autonomic nerve function in daily life.

  Mizuno K, Sasaki AT, Ebisu K, Tajima K, Kajimoto O, Nojima J, Kuratsune H, Hori H, Watanabe Y

  Health and a vibrant life are sought by everyone. To improve quality of life (QOL), maintain a healthy state, and prevent various diseases, evaluations of the effects of potentially QOL-increasing factors are important. Chronic oxidative stress and inflammation cause deteriorations in central nervous system function, leading to low QOL. In healthy individuals, aging, job stress, and cognitive load over several hours also induce increases in oxidative stress, suggesting that preventing the accumulation of oxidative stress caused by daily stress and daily work contributes to maintaining QOL and ameliorating the effects of aging. Hydrogen has anti-oxidant activity and can prevent inflammation, and may thus contribute to improve QOL. The present study aimed to investigate the effects of drinking hydrogen-rich water (HRW) on the QOL of adult volunteers using psychophysiological tests, including questionnaires and tests of autonomic nerve function and cognitive function. In this double-blinded, placebo-controlled study with a two-way crossover design, 26 volunteers (13 females, 13 males; mean age, 34.4 ± 9.9 years) were randomized to either a group administered oral HRW (600 mL/d) or placebo water (PLW, 600 mL/d) for 4 weeks. Change ratios (post-treatment/pre-treatment) for K6 score and sympathetic nerve activity during the resting state were significantly lower after HRW administration than after PLW administration. These results suggest that HRW may reinforce QOL through effects that increase central nervous system functions involving mood, anxiety, and autonomic nerve function.

  2018, Med Gas Res., 7(4) (4), 247 - 255, English, International magazine

  [Refereed]

  Scientific journal


• Comparison of pharmacokinetics of newly discovered aromatase inhibitors by a cassette microdosing approach in healthy Japanese subjects.

  Hiroyuki Kusuhara, Tadayuki Takashima, Hisako Fujii, Tsutomu Takashima, Masaaki Tanaka, Akira Ishii, Shusaku Tazawa, Kazuhiro Takahashi, Kayo Takahashi, Hidekichi Tokai, Tsuneo Yano, Makoto Kataoka, Akihiro Inano, Suguru Yoshida, Takamitsu Hosoya, Yuichi Sugiyama, Shinji Yamashita, Taisuke Hojo, Yasuyoshi Watanabe

  The aim of the present study is to investigate the pharmacokinetics of our newly developed aromatase inhibitors (cetrozole and TMD-322) in healthy subjects by a cassette microdose strategy. A cocktail of cetrozole and TMD-322 was administered intravenously or orally (1.98 μg for each drug) to six healthy volunteers in a crossover fashion. Anastrozole (1.98 μg) was also included in the oral cocktail. Total body clearance and bioavailability were 12.1 ± 7.1 mL/min/kg and 34.9 ± 32.3% for cetrozole, and 16.8 ± 3.5 mL/min/kg and 18.4 ± 12.2% for TMD-322, respectively. The area under the plasma concentration-time curves of cetrozole and TMD-322 after oral administration was markedly lower than that of anastrozole because of their high hepatic clearance. Two subjects out of six exhibited 4- and 17-fold larger exposure of cetrozole than the others following intravenous and oral administration, respectively. Such variation was not observed for TMD-322 and anastrozole. Extensive metabolism of cetrozole and TMD-322 was observed in the CYP2C19 expression system among the test CYP isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4). We report the first clinical investigation of our aromatase inhibitors by a cassette microdose strategy in healthy Japanese subjects. This strategy offers an optional approach for candidate selection as a phase zero study in drug development.

  Dec. 2017, Drug metabolism and pharmacokinetics, 32(6) (6), 293 - 300, English, International magazine

  Scientific journal


• Evidence for unconscious regulation of performance in fatigue.

  Akira Ishii, Masaaki Tanaka, Takahiro Yoshikawa, Yasuyoshi Watanabe

  Since fatigue is prevalent in modern societies, it is necessary to clarify the neural mechanisms of fatigue. The regulation of performance through fatigue sensation is one of the mechanisms that decreases performance in fatigue. However, it is unknown whether subjective feeling of fatigue is necessary for the regulation of performance. Here, we examined whether decreased performance occurs without increased fatigue sensation through the experiment which was designed to test if fatigue can be learned unconsciously. Healthy male volunteers performed a fatigue-inducing hand-grip task for 10 min while viewing a target image presented without awareness. On the next day, they viewed a control and the target images presented with awareness and the neural activity caused by viewing the images was measured using magnetoencephalography. Results showed the level of fatigue sensation was not altered but grip-strength was decreased by viewing the target image on the second day. The level of beta band power in Brodmann's area 31 was increased by viewing the target image and this increase was negatively associated with the decrease of grip-strength caused in the hand-grip task. These findings demonstrated that fatigue can be learned unconsciously and that there is a mechanism to decrease performance without fatigue sensation.

  Nov. 2017, Scientific reports, 7(1) (1), 16103 - 16103, English, International magazine

  Scientific journal


• Visualization of HER2-specific breast cancer intratumoral heterogeneity using 64Cu-DOTA-trastuzumab PET.

  Shinsuke Sasada, Hiroaki Kurihara, Takayuki Kinoshita, Masayuki Yoshida, Natsuki Honda, Tatsunori Shimoi, Akihiko Shimomura, Kan Yonemori, Chikako Shimizu, Akinobu Hamada, Yousuke Kanayama, Yasuyoshi Watanabe, Yasuhiro Fujiwara, Kenji Tamura

  Nov. 2017, European journal of nuclear medicine and molecular imaging, 44(12) (12), 2146 - 2147, English, International magazine

  Scientific journal


• Development of Diagnostic Techniques for Early Rheumatoid Arthritis Using Positron Emission Tomography with [11C]PK11195 and [11C]Ketoprofen Tracers.

  Satoshi Nozaki, Naoko Ozaki, Shinobu Suzuki, Miki Goto, Aya Mawatari, Yuka Nakatani, Emi Hayashinaka, Yasuhiro Wada, Hisashi Doi, Yasuyoshi Watanabe

  PURPOSE: In vivo detection of pathological insults during the early stages of rheumatoid synovitis is essential to allow early anti-inflammatory treatment for prevention of joint destruction. Whether rheumatoid synovitis pathology and the efficacy of therapies can be visualized by positron emission tomography (PET) tracers specific to the inflammatory process was investigated. PROCEDURES: Using a collagen-induced experimental rat model of rheumatoid arthritis, in vivo imaging using the PET tracers [11C]PK11195, which binds to the translocator protein mainly expressed on myeloid cells, and [11C]ketoprofen, for cyclooxygenase imaging, was performed. To evaluate therapeutic efficacy, model animals were administered the tumour necrosis factor alpha blocker etanercept subcutaneously. RESULTS: [11C]PK11195 and [11C]ketoprofen uptakes were significantly higher in inflamed paws of collagen-induced arthritis rats than in normal rats. The data showed a correlation between tracer uptake values and paw swelling. After treatment with etanercept, [11C]ketoprofen uptake was significantly lower in treated animals than in untreated ones, whereas [11C]PK11195 uptake in the inflamed regions was comparable to that in the untreated group. CONCLUSIONS: With [11C]PK11195 and [11C]ketoprofen tracers, non-invasive in vivo PET imaging for rheumatoid synovitis can provide diagnostic evidence of early synovitis and allow monitoring inflammatory cell activity during treatment.

  Oct. 2017, Molecular imaging and biology, 19(5) (5), 746 - 753, English, International magazine

  Scientific journal


• Positron emission tomography with additional γ-ray detectors for multiple-tracer imaging.

  Tomonori Fukuchi, Takashi Okauchi, Mika Shigeta, Seiichi Yamamoto, Yasuyoshi Watanabe, Shuichi Enomoto

  PURPOSE: Positron emission tomography (PET) is a useful imaging modality that quantifies the physiological distributions of radiolabeled tracers in vivo in humans and animals. However, this technique is unsuitable for multiple-tracer imaging because the annihilation photons used for PET imaging have a fixed energy regardless of the selection of the radionuclide tracer. This study developed a multi-isotope PET (MI-PET) system and evaluated its imaging performance. METHODS: Our MI-PET system is composed of a PET system and additional γ-ray detectors. The PET system consists of pixelized gadolinium orthosilicate (GSO) scintillation detectors and has a ring geometry that is 95 mm in diameter with an axial field of view of 37.5 mm. The additional detectors are eight bismuth germanium oxide (BGO) scintillation detectors, each of which is 50 × 50 × 30 mm3 , arranged into two rings mounted on each side of the PET ring with a 92-mm-inner diameter. This system can distinguish between different tracers using the additional γ-ray detectors to observe prompt γ-rays, which are emitted after positron emission and have an energy intrinsic to each radionuclide. Our system can simultaneously acquire double- (two annihilation photons) and triple- (two annihilation photons and a prompt γ-ray) coincidence events. The system's efficiency for detecting prompt de-excitation γ-rays was measured using a positron-γ emitter, 22 Na. Dual-radionuclide (18 F and 22 Na) imaging of a rod phantom and a mouse was performed to demonstrate the performance of the developed system. Our system's basic performance was evaluated by reconstructing two images, one containing both tracers and the other containing just the second tracer, from list-mode data sets that were categorized by the presence or absence of the prompt γ-ray. RESULTS: The maximum detection efficiency for 1275 keV γ-rays emitted from 22 Na was approximately 7% at the scanner's center, and the minimum detection efficiency was 5.1% at the edge of the field of view. Dual-radionuclide imaging of the point sources and rod phantom revealed that our system maintained PET's intrinsic spatial resolution and quantitative nature for the second tracer. We also successfully acquired simultaneous double- and triple-coincidence events from a mouse containing 18 F-fluoro-deoxyglucose and 22 Na dissolved in water. The dual-tracer distributions in the mouse obtained by our MI-PET were reasonable from the viewpoints of physiology and pharmacokinetics. CONCLUSIONS: This study demonstrates the feasibility of multiple-tracer imaging using PET with additional γ-ray detectors. This method holds promise for enabling the reconstruction of quantitative multiple-tracer images and could be very useful for analyzing multiple-molecular dynamics.

  Jun. 2017, Medical physics, 44(6) (6), 2257 - 2266, English, International magazine

  Scientific journal


• Serotonin rebalances cortical tuning and behavior linked to autism symptoms in 15q11-13 CNV mice.

  Nobuhiro Nakai, Masatoshi Nagano, Fumihito Saitow, Yasuhito Watanabe, Yoshinobu Kawamura, Akiko Kawamoto, Kota Tamada, Hiroshi Mizuma, Hirotaka Onoe, Yasuyoshi Watanabe, Hiromu Monai, Hajime Hirase, Jin Nakatani, Hirofumi Inagaki, Tomoyuki Kawada, Taisuke Miyazaki, Masahiko Watanabe, Yuka Sato, Shigeo Okabe, Kazuo Kitamura, Masanobu Kano, Kouichi Hashimoto, Hidenori Suzuki, Toru Takumi

  Serotonin is a critical modulator of cortical function, and its metabolism is defective in autism spectrum disorder (ASD) brain. How serotonin metabolism regulates cortical physiology and contributes to the pathological and behavioral symptoms of ASD remains unknown. We show that normal serotonin levels are essential for the maintenance of neocortical excitation/inhibition balance, correct sensory stimulus tuning, and social behavior. Conversely, low serotonin levels in 15q dup mice (a model for ASD with the human 15q11-13 duplication) result in impairment of the same phenotypes. Restoration of normal serotonin levels in 15q dup mice revealed the reversibility of a subset of ASD-related symptoms in the adult. These findings suggest that serotonin may have therapeutic potential for discrete ASD symptoms.

  Jun. 2017, Science advances, 3(6) (6), e1603001, English, International magazine

  Scientific journal


• PETイメージングによる64Cu標識エクソソームの動態評価

  藁科 翔太, 造田 真希, 和田 康弘, 渡辺 恭良, 向井 英史

  日本DDS学会, Jun. 2017, 日本DDS学会学術集会プログラム予稿集, 33回, 198 - 198, Japanese


• Palladium(II)-Mediated Rapid C-11-Cyanation of Aryl Borons: a General Method for the Synthesis of PET Tracers with a [cyano-C-11]Cyanoarene Structure

  Zhouen Zhang, Takashi Niwa, Yasuyoshi Watanabe, Takamitsu Hosoya

  May 2017, JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS, 60, S45 - S45, English


• 標的性を付与した先駆的医薬品の開発と評価 創薬・DDS評価におけるPETイメージングの活用

  向井 英史, 渡辺 恭良

  (公社)日本薬剤学会, May 2017, 日本薬剤学会年会講演要旨集, 32年会, 31 - 31, Japanese


• [18F]DPA-714 PETイメージングによる神経炎症の定量的評価

  金子 健一, 馬渡 彩, 入江 さつき, 胡 迪, 中岡 貴義, 林中 恵美, 和田 康弘, 土居 久志, 崔 翼龍, 渡辺 恭良

  日本分子イメージング学会, May 2017, JSMI Report, 10(2) (2), 159 - 159, Japanese


• 内側前脳束の脳内自己刺激後における脳内糖代謝変容部位の検索

  岡内 隆, 武 玉萍, 重田 美香, 林中 恵美, 和田 康弘, 渡辺 恭良, 崔 翼龍

  日本分子イメージング学会, May 2017, JSMI Report, 10(2) (2), 163 - 163, Japanese


• 動物モデル 新しい慢性疲労モデルの確立および慢性化形成に関わる血中ホルモンの動態変化の解析

  胡 迪, 李 丹渓, 重田 美香, 岡内 隆, 渡邊 恭良, 崔 翼龍

  日本疲労学会, May 2017, 日本疲労学会誌, 13(1) (1), 54 - 54, Japanese


• ラットの慢性中枢性疲労発生期における体温調節システムの機能的変化(Functional change of the thermoregulatory system during chronic fatigue formation in rats)

  李 丹渓, 胡 迪, 重田 美香, 岡内 隆, 李 峰, 渡邊 恭良, 崔 翼龍

  日本疲労学会, May 2017, 日本疲労学会誌, 13(1) (1), 101 - 101, English


• In Vivo Gold Complex Catalysis within Live Mice.

  Kazuki Tsubokura, Kenward K H Vong, Ambara R Pradipta, Akihiro Ogura, Sayaka Urano, Tsuyoshi Tahara, Satoshi Nozaki, Hirotaka Onoe, Yoichi Nakao, Regina Sibgatullina, Almira Kurbangalieva, Yasuyoshi Watanabe, Katsunori Tanaka

  Metal complex catalysis within biological systems is largely limited to cell and bacterial systems. In this work, a glycoalbumin-AuIII complex was designed and developed that enables organ-specific, localized propargyl ester amidation with nearby proteins within live mice. The targeted reactivity can be imaged through the use of Cy7.5- and TAMRA-linked propargyl ester based fluorescent probes. This targeting system could enable the exploitation of other metal catalysis strategies for biomedical and clinical applications.

  Mar. 2017, Angewandte Chemie (International ed. in English), 56(13) (13), 3579 - 3584, English, International magazine

  Scientific journal


• PETによる体内動態解析を指向したエクソソーム表面への64Cu標識

  藁科 翔太, 造田 真希, 仁 欽, 渡辺 恭良, 向井 英史

  (公社)日本薬学会, Mar. 2017, 日本薬学会年会要旨集, 137年会(4) (4), 91 - 91, Japanese


• がん治療用細菌マシンを目的としたRGDペプチド提示大腸菌の作製とがん細胞に対する相互作用の評価

  高橋 麻衣子, 渡辺 恭良, 向井 英史

  (公社)日本薬学会, Mar. 2017, 日本薬学会年会要旨集, 137年会(4) (4), 98 - 98, Japanese


• NG2 glial cells regulate neuroimmunological responses to maintain neuronal function and survival.

  Masayuki Nakano, Yasuhisa Tamura, Masanori Yamato, Satoshi Kume, Asami Eguchi, Kumi Takata, Yasuyoshi Watanabe, Yosky Kataoka

  NG2-expressing neural progenitor cells (i.e., NG2 glial cells) maintain their proliferative and migratory activities even in the adult mammalian central nervous system (CNS) and produce myelinating oligodendrocytes and astrocytes. Although NG2 glial cells have been observed in close proximity to neuronal cell bodies in order to receive synaptic inputs, substantive non-proliferative roles of NG2 glial cells in the adult CNS remain unclear. In the present study, we generated NG2-HSVtk transgenic rats and selectively ablated NG2 glial cells in the adult CNS. Ablation of NG2 glial cells produced defects in hippocampal neurons due to excessive neuroinflammation via activation of the interleukin-1 beta (IL-1β) pro-inflammatory pathway, resulting in hippocampal atrophy. Furthermore, we revealed that the loss of NG2 glial cell-derived hepatocyte growth factor (HGF) exacerbated these abnormalities. Our findings suggest that NG2 glial cells maintain neuronal function and survival via the control of neuroimmunological function.

  Feb. 2017, Scientific reports, 7, 42041 - 42041, English, International magazine

  Scientific journal


• Sequential Double "Clicks" toward Structurally Well-Defined Heterogeneous N-Glycoclusters: The Importance of Cluster Heterogeneity on Pattern Recognition In Vivo.

  Liliya Latypova, Regina Sibgatullina, Akihiro Ogura, Katsumasa Fujiki, Alsu Khabibrakhmanova, Tsuyoshi Tahara, Satoshi Nozaki, Sayaka Urano, Kazuki Tsubokura, Hirotaka Onoe, Yasuyoshi Watanabe, Almira Kurbangalieva, Katsunori Tanaka

  Structurally well-defined heterogeneous N-glycoclusters are prepared on albumin via a double click procedure. The number of glycan molecules present, in addition to the spatial arrangement of glycans in the heterogeneous glycoclusters, plays an important role in the in vivo kinetics and organ-selective accumulation through glycan pattern recognition mechanisms.

  Feb. 2017, Advanced science (Weinheim, Baden-Wurttemberg, Germany), 4(2) (2), 1600394 - 1600394, English, International magazine

  Scientific journal


• Localized Accumulation of Tau without Amyloid-Beta in Aged Brains Measured with [11C]PBB3 and [11C]Pib Positron Emission Tomography

  Takayuki Kikukawa, Haruna Saito, Itsuki Hasegawa, Jun Takeuchi, Akitoshi Takeda, Joji Kawabe, Yasuhiro Wada, Aya Mawatari, Yasuyoshi Watanabe, Soichiro Kitamura, Hitoshi Shimada, Makoto Higuchi, Tetsuya Suhara, Yoshiaki Itoh

  OMICS Publishing Group, 2017, Journal of Alzheimer’s Disease & Parkinsonism, 07(06) (06)

  Scientific journal


• Music Improves Subjective Feelings Leading to Cardiac Autonomic Nervous Modulation: A Pilot Study.

  Satoshi Kume, Yukako Nishimura, Kei Mizuno, Nae Sakimoto, Hiroshi Hori, Yasuhisa Tamura, Masanori Yamato, Rika Mitsuhashi, Keigo Akiba, Jun-Ichi Koizumi, Yasuyoshi Watanabe, Yosky Kataoka

  It is widely accepted that listening to music improves subjective feelings and reduces fatigue sensations, and different kinds of music lead to different activations of these feelings. Recently, cardiac autonomic nervous modulation has been proposed as a useful objective indicator of fatigue. However, scientific considerations of the relation between feelings of fatigue and cardiac autonomic nervous modulation while listening to music are still lacking. In this study, we examined which subjective feelings of fatigue are related to participants' cardiac autonomic nervous function while they listen to music. We used an album of comfortable and relaxing environmental music, with blended sounds from a piano and violin as well as natural sound sources. We performed a crossover trial of environmental music and silent sessions for 20 healthy subjects, 12 females, and 8 males, after their daily work shift. We measured changes in eight types of subjective feelings, including healing, fatigue, sleepiness, relaxation, and refreshment, using the KOKORO scale, a subjective mood measurement system for self-reported feelings. Further, we obtained measures of cardiac autonomic nervous function on the basis of heart rate variability before and after the sessions. During the music session, subjective feelings significantly shifted toward healing and a secure/relaxed feeling and these changes were greater than those in the silent session. Heart rates (ΔHR) in the music session significantly decreased compared with those in the silent session. Other cardiac autonomic parameters such as high-frequency (HF) component and the ratio of low-frequency (LF) and HF components (LF/HF) were similar in the two sessions. In the linear regression analysis of the feelings with ΔHR and changes in LF/HF (ΔLF/HF), increases and decreases in ΔHR were correlated to the feeling axes of Fatigue-Healing and Anxiety/Tension-Security/Relaxation, whereas those in ΔLF/HF were related to the feeling axes of Sleepiness-Wakefulness and Gloomy-Refreshed. This indicated that listening to music improved the participants' feelings of fatigue and decreased their heart rates. However, it did not reduce the cardiac LF/HF, suggesting that cardiac LF/HF might show a delayed response to fatigue. Thus, we demonstrated changes in cardiac autonomic nervous functions based on feelings of fatigue.

  2017, Frontiers in neuroscience, 11, 108 - 108, English, International magazine

  Scientific journal


• Neural basis of individual differences in the response to mental stress: a magnetoencephalography study.

  Emi Yamano, Akira Ishii, Masaaki Tanaka, Shusaku Nomura, Yasuyoshi Watanabe

  Stress is a risk factor for the onset of mental disorders. Although stress response varies across individuals, the mechanism of individual differences remains unclear. Here, we investigated the neural basis of individual differences in response to mental stress using magnetoencephalography (MEG). Twenty healthy male volunteers completed the Temperament and Character Inventory (TCI). The experiment included two types of tasks: a non-stress-inducing task and a stress-inducing task. During these tasks, participants passively viewed non-stress-inducing images and stress-inducing images, respectively, and MEG was recorded. Before and after each task, MEG and electrocardiography were recorded and subjective ratings were obtained. We grouped participants according to Novelty seeking (NS) - tendency to be exploratory, and Harm avoidance (HA) - tendency to be cautious. Participants with high NS and low HA (n = 10) assessed by TCI had a different neural response to stress than those with low NS and high HA (n = 10). Event-related desynchronization (ERD) in the beta frequency band was observed only in participants with high NS and low HA in the brain region extending from Brodmann's area 31 (including the posterior cingulate cortex and precuneus) from 200 to 350 ms after the onset of picture presentation in the stress-inducing task. Individual variation in personality traits (NS and HA) was associated with the neural response to mental stress. These findings increase our understanding of the psychological and neural basis of individual differences in the stress response, and will contribute to development of the psychotherapeutic approaches to stress-related disorders.

  Dec. 2016, Brain imaging and behavior, 10(4) (4), 1160 - 1171, English, International magazine

  Scientific journal


• Blood-brain barrier permeability of ginkgolide: Comparison of the behavior of PET probes 7α-[18F]fluoro- and 10-O-p-[11C]methylbenzyl ginkgolide B in monkey and rat brains.

  Hisashi Doi, Kengo Sato, Hideo Shindou, Kengo Sumi, Hiroko Koyama, Takamitsu Hosoya, Yasuyoshi Watanabe, Satoshi Ishii, Hideo Tsukada, Koji Nakanishi, Masaaki Suzuki

  The blood-brain barrier permeability of ginkgolide B was examined using positron emission tomography (PET) probes of a 18F-incorporated ginkgolide B ([18F]-2) and a 11C-incorporated methylbenzyl-substituted ginkgolide B ([11C]-3). PET studies in monkeys showed low uptake of [18F]-2 into the brain, but small amounts of [11C]-3 were accumulated in the parenchyma. Furthermore, when cyclosporine A was preadministered to rats, the accumulation of [18F]-2 in the rat brain did not significantly change, however, the accumulation of [11C]-3 was five times higher than that in the control rat. These results provide effective approaches for investigating the drug potential of ginkgolides.

  Nov. 2016, Bioorganic & medicinal chemistry, 24(21) (21), 5148 - 5157, English, International magazine

  Scientific journal


• Index markers of chronic fatigue syndrome with dysfunction of TCA and urea cycles.

  Emi Yamano, Masahiro Sugimoto, Akiyoshi Hirayama, Satoshi Kume, Masanori Yamato, Guanghua Jin, Seiki Tajima, Nobuhito Goda, Kazuhiro Iwai, Sanae Fukuda, Kouzi Yamaguti, Hirohiko Kuratsune, Tomoyoshi Soga, Yasuyoshi Watanabe, Yosky Kataoka

  Chronic fatigue syndrome (CFS) is a persistent and unexplained pathological state characterized by exertional and severely debilitating fatigue, with/without infectious or neuropsychiatric symptoms, lasting at least 6 consecutive months. Its pathogenesis remains incompletely understood. Here, we performed comprehensive metabolomic analyses of 133 plasma samples obtained from CFS patients and healthy controls to establish an objective diagnosis of CFS. CFS patients exhibited significant differences in intermediate metabolite concentrations in the tricarboxylic acid (TCA) and urea cycles. The combination of ornithine/citrulline and pyruvate/isocitrate ratios discriminated CFS patients from healthy controls, yielding area under the receiver operating characteristic curve values of 0.801 (95% confidential interval [CI]: 0.711-0.890, P < 0.0001) and 0.750 (95% CI: 0.584-0.916, P = 0.0069) for training (n = 93) and validation (n = 40) datasets, respectively. These findings provide compelling evidence that a clinical diagnostic tool could be developed for CFS based on the ratios of metabolites in plasma.

  Oct. 2016, Scientific reports, 6, 34990 - 34990, English, International magazine

  Scientific journal


• Visual food stimulus changes resting oscillatory brain activities related to appetitive motive.

  Takahiro Yoshikawa, Masaaki Tanaka, Akira Ishii, Yoko Yamano, Yasuyoshi Watanabe

  Sep. 2016, Behavioral and brain functions : BBF, 12(1) (1), 26 - 26, English, International magazine

  Scientific journal


• The neural mechanisms of re-experiencing physical fatigue sensation: a magnetoencephalography study.

  Akira Ishii, Masaaki Tanaka, Yasuyoshi Watanabe

  It has been hypothesized that fatigue sensation impairs the ability and efficiency to perform activities and can be a cause of fatigue itself. As such, it is important to clarify the neural mechanisms of fatigue sensation. The re-experiencing of mental fatigue sensation involves brain regions including Brodmann's area (BA) 40, BA 39, and the pulvinar nucleus. In the present study, we examined neural activity caused by re-experiencing a physical fatigue sensation that had been experienced. Fifteen healthy male volunteers participated in fatigue and control experiments in a crossover fashion. In the fatigue experiment, participants performed a handgrip task for 10 min to induce a physical fatigue sensation and then re-experienced the physical fatigue sensation during magnetoencephalography (MEG) session. In the control experiment, they did not perform the handgrip task but re-experienced the sensation without physical fatigue in an MEG session. Neural activity related to re-experiencing physical fatigue sensations of the right hand (right condition), left hand (left condition), and related to listening to the auditory cues (sound condition) was assessed using spatial filtering analyses of the MEG data. Changes in oscillatory band power in some brain regions, including BA 40, were common between the right and left conditions. A part of the neural activity related to the re-experiencing physical fatigue sensation, such as the decrease in alpha (8-13 Hz) band power in the BA 40, was also observed in the sound condition. These findings may help to understand the neural mechanisms related to intentionally and unintentionally re-experiencing physical fatigue sensation.

  Sep. 2016, Experimental brain research, 234(9) (9), 2433 - 46, English, International magazine

  Scientific journal


• Noninvasive Evaluation of Cellular Proliferative Activity in Brain Neurogenic Regions in Rats under Depression and Treatment by Enhanced [18F]FLT-PET Imaging.

  Yasuhisa Tamura, Kayo Takahashi, Kumi Takata, Asami Eguchi, Masanori Yamato, Satoshi Kume, Masayuki Nakano, Yasuyoshi Watanabe, Yosky Kataoka

  UNLABELLED: Neural stem cells in two neurogenic regions, the subventricular zone and the subgranular zone (SGZ) of the hippocampal dentate gyrus, can divide and produce new neurons throughout life. Hippocampal neurogenesis is related to emotions, including depression/anxiety, and the therapeutic effects of antidepressants, as well as learning and memory. The establishment of in vivo imaging for proliferative activity of neural stem cells in the SGZ might be used to diagnose depression and to monitor the therapeutic efficacy of antidepressants. Positron emission tomography (PET) imaging with 3'-deoxy-3'-[(18)F]fluoro-l-thymidine ([(18)F]FLT) has been studied to allow visualization of proliferative activity in two neurogenic regions of adult mammals; however, the PET imaging has not been widely used because of lower accumulation of [(18)F]FLT, which does not allow quantitative assessment of the decline in cellular proliferative activity in the SGZ under the condition of depression. We report the establishment of an enhanced PET imaging method with [(18)F]FLT combined with probenecid, an inhibitor of drug transporters at the blood-brain barrier, which can allow the quantitative visualization of neurogenic activity in rats. Enhanced PET imaging allowed us to evaluate reduced cell proliferation in the SGZ of rats with corticosterone-induced depression, and further the recovery of proliferative activity in rats under treatment with antidepressants. This enhanced [(18)F]FLT-PET imaging technique with probenecid can be used to assess the dynamic alteration of neurogenic activity in the adult mammalian brain and may also provide a means for objective diagnosis of depression and monitoring of the therapeutic effect of antidepressant treatment. SIGNIFICANCE STATEMENT: Adult hippocampal neurogenesis may play a role in major depression and antidepressant therapy. Establishment of in vivo imaging for hippocampal neurogenic activity may be useful to diagnose depression and monitor the therapeutic efficacy of antidepressants. Positron emission tomography (PET) imaging has been studied to allow visualization of neurogenic activity; however, PET imaging has not been widely used due to the lower accumulation of the PET tracer in the neurogenic regions. Here, we succeeded in establishing highly quantitative PET imaging for neurogenic activity in adult brain with an inhibitor for drug transporter. This enhanced PET imaging allowed evaluation of the decline of neurogenic activity in the hippocampus of rats with depression and the recovery of neurogenic activity by antidepressant treatment.

  Aug. 2016, The Journal of neuroscience : the official journal of the Society for Neuroscience, 36(31) (31), 8123 - 31, English, International magazine

  Scientific journal


• Ubiquinol-10 supplementation improves autonomic nervous function and cognitive function in chronic fatigue syndrome.

  Sanae Fukuda, Junzo Nojima, Osami Kajimoto, Kouzi Yamaguti, Yasuhito Nakatomi, Hirohiko Kuratsune, Yasuyoshi Watanabe

  The aim of this study was to evaluate the benefit of oral ubiquinol-10 supplementation in CFS patients using an open-label study and a randomized, double-blinded, placebo-controlled (RCT) study. Twenty patients with CFS were randomly enrolled in an 8-week open-label oral ubiquinol-10 (150 mg ubiquinol-10/day) study. The patients and the attending physicians were not blinded to the supplementation. Forty-three patients with CFS were randomly assigned to receive either ubiquinol-10 (150 mg/day) or placebo every day for 12 weeks. The patients and the attending physicians were blinded to the supplementation, and a total of 31 patients (N = 17 in the ubiquinol group and 14 in the placebo group) completed the study. The beneficial effects of ubiquinol-10 were observed in the open-label study we conducted prior to the RCT. The RCT results suggest that supplementation with ubiquinol-10 for 12 weeks is effective for improving several CFS symptoms. © 2016 BioFactors, 42(4):431-440, 2016.

  Jul. 2016, BioFactors (Oxford, England), 42(4) (4), 431 - 40, English, International magazine

  Scientific journal


• Usefulness of standardized uptake value normalized by individual CT-based lean body mass in application of PET response criteria in solid tumors (PERCIST).

  Atsushi Narita, Susumu Shiomi, Yutaka Katayama, Takashi Yamanaga, Hiromitsu Daisaki, Kazuo Hamada, Yasuyoshi Watanabe

  Our aim in this study was to verify the usefulness of the standardized uptake value (SUV) normalized by individual CT-based lean body mass (LBMCT) in application of PET response criteria in solid tumors (PERCIST).We retrospectively investigated 14 patients (4 male and 10 female) with malignant lymphoma who were undergoing chemotherapy. (18)F-FDG PET/CT examinations were performed before and after chemotherapy. The LBMCT was calculated by estimation of fat weight from CT data (from skull base to pelvis). The mean ± standard deviation (SD) and the Bland-Altman plot were used for comparison among body weight, LBMCT, and LBM derived from a predictive equation (LBMPE). Indices for FDG uptake in the liver were: SUV, SUV based on LBMPE (SULPE), and SUV based on LBMCT (SULCT). Overall differences between the uptake values were analyzed by one-way ANOVA. If the ANOVA showed significance, differences between uptake values were investigated further by use of the Tukey-Kramer test. The mean values of body weight, LBMPE, and LBMCT were: 55.4 ± 14.9 (39.0-112.0), 43.0 ± 10.5 (31.3-75.2), and 35.3 ± 9.8 (23.4-75.8) kg, respectively. There was a wide dispersion between LBMPE and LBMCT (differences, 7.6 ± 3.6 kg; 95 % CI, 6.42-8.85). LBMPE was higher than LBMCT in all the cases except in Case 11. The mean uptake values significantly differed among SUV, SULPE, and SULCT (F = 68.3, p < 0.05). Whereas SULPE deviated from PERCIST criteria in seven patients, SULCT satisfied the criteria except in one case. These results suggest that liver SULCT is useful for application of PERCIST.

  Jul. 2016, Radiological physics and technology, 9(2) (2), 170 - 7, English, Domestic magazine

  Scientific journal


• Exploratory human PET study of the effectiveness of (11)C-ketoprofen methyl ester, a potential biomarker of neuroinflammatory processes in Alzheimer's disease.

  Akihito Ohnishi, Michio Senda, Tomohiko Yamane, Tomoko Mikami, Hiroyuki Nishida, Tomoyuki Nishio, Go Akamatsu, Yasuhiko Ikari, Shogo Kimoto, Kazuki Aita, Masahiro Sasaki, Hiroko Shinkawa, Yasuji Yamamoto, Miho Shukuri, Aya Mawatari, Hisashi Doi, Yasuyoshi Watanabe, Hirotaka Onoe

  INTRODUCTION: Neuroinflammatory processes play an important role in the pathogenesis of Alzheimer's disease (AD). As a biomarker of neuroinflammatory processes, we designed (11)C-labeled ketoprofen methyl ester ([(11)C]KTP-Me) to increase the blood-brain barrier permeability of ketoprofen (KTP), a selective cyclooxygenase-1 (COX-1) inhibitor. Animal studies indicated that [(11)C]KTP-Me enters the brain and accumulates in activated microglia of inflammatory lesions. In a first-in-human study, we reported that [(11)C]KTP-Me is a safe positron emission tomography (PET) tracer and enters the brain; the radioactivity is washed out from normal cerebral tissue. Here we explored the efficacy of [(11)C]KTP-Me as a diagnostic biomarker of neuroinflammatory processes in AD. METHODS: [(11)C]KTP-Me was synthesized by rapid C-[(11)C]methylation of [(11)C]CH3I and the corresponding arylacetate precursor. Nine subjects (four healthy subjects, two Pittsburgh compound-B (PiB)-positive patients with mild cognitive impairment (MCI), and three PiB-positive AD patients) underwent a dynamic brain PET scan for 70min after injection. We evaluated differences in cortical retention and washout rate in the brain between healthy subjects and MCI/AD patients. RESULTS: A brain distribution pattern reflecting blood flow in the early-phase image was seen in both healthy subjects and MCI/AD patients. Cortical activity gradually cleared in all groups. However, we observed no obvious difference in the washout rate between healthy subjects and MCI/AD patients or between MCI and AD patients. CONCLUSIONS: [(11)C]KTP-Me cannot be useful as a potential diagnostic biomarker for MCI/AD. Further improvements in binding affinity and specificity, etc., are needed to be a diagnostic biomarker of neuroinflammation in AD. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: [(11)C]KTP-Me is a new tracer that targets COX-1. [(11)C]KTP-Me is expected to be a diagnostic biomarker of neuroinflammation in AD in the future. The effectiveness was limited in a small number of AD patients. Therefore, further studies are needed to clarify the usefulness of [(11)C]KTP-Me.

  Jul. 2016, Nuclear medicine and biology, 43(7) (7), 438 - 44, English, International magazine

  Scientific journal


• A potential biomarker for fatigue: Oxidative stress and anti-oxidative activity.

  Sanae Fukuda, Junzo Nojima, Yukari Motoki, Kouzi Yamaguti, Yasuhito Nakatomi, Naoko Okawa, Kazumi Fujiwara, Yasuyoshi Watanabe, Hirohiko Kuratsune

  We sought to determine whether oxidative stress and anti-oxidative activity could act as biomarkers that discriminate patients with chronic fatigue syndrome (CFS) from healthy volunteers at acute and sub-acute fatigue and resting conditions. We calculated the oxidative stress index (OSI) from reactive oxygen metabolites-derived compounds (d-ROMs) and the biological antioxidant potential (BAP). We determined changes in d-ROMs, BAP, and OSI in acute and sub-acute fatigue in two healthy groups, and compared their values at rest between patients with CFS (diagnosed by Fukuda 1994 criteria) and another group of healthy controls. Following acute fatigue in healthy controls, d-ROMs and OSI increased, and BAP decreased. Although d-ROMs and OSI were significantly higher after sub-acute fatigue, BAP did not decrease. Resting condition yielded higher d-ROMs, higher OSI, and lower BAP in patients with CFS than in healthy volunteers, but lower d-ROMs and OSI when compared with sub-acute controls. BAP values did not significantly differ between patients with CFS and controls in the sub-acute condition. However, values were significantly higher than in the resting condition for controls. Thus, measured of oxidative stress (d-ROMS) and anti-oxidative activity (BAP) might be useful for discriminating acute, sub-acute, and resting fatigue in healthy people from patients with CFS, or for evaluating fatigue levels in healthy people.

  Jul. 2016, Biological psychology, 118, 88 - 93, English, International magazine

  Scientific journal


• In vivo imaging of advanced glycation end products (AGEs) of albumin: first observations of significantly reduced clearance and liver deposition properties in mice.

  Ayumi Tsutsui, Akihiro Ogura, Tsuyoshi Tahara, Satoshi Nozaki, Sayaka Urano, Mitsuko Hara, Soichi Kojima, Almira Kurbangalieva, Hirotaka Onoe, Yasuyoshi Watanabe, Naoyuki Taniguchi, Katsunori Tanaka

  Advanced glycation end products (AGEs) are associated with various diseases, especially during aging and the development of diabetes and uremia. To better understand these biological processes, investigation of the in vivo kinetics of AGEs, i.e., analysis of trafficking and clearance properties, was carried out by molecular imaging. Following the preparation of Cy7.5-labeled AGE-albumin and intravenous injection in BALB/cA-nu/nu mice, noninvasive fluorescence kinetics analysis was performed. In vivo imaging and fluorescence microscopy analysis revealed that non-enzymatic AGEs were smoothly captured by scavenger cells in the liver, i.e., Kupffer and other sinusoidal cells, but were unable to be properly cleared from the body. Overall, these results highlight an important link between AGEs and various disorders associated with them, which may serve as a platform for future research to better understand the processes and mechanisms of these disorders.

  Jun. 2016, Organic & biomolecular chemistry, 14(24) (24), 5755 - 60, English, International magazine

  Scientific journal


• Glycan multivalency effects toward albumin enable N-glycan-dependent tumor targeting.

  Akihiro Ogura, Tsuyoshi Tahara, Satoshi Nozaki, Hirotaka Onoe, Almira Kurbangalieva, Yasuyoshi Watanabe, Katsunori Tanaka

  Multivalent interactions play an essential role in molecular recognition in living systems. These effects were employed to target tumor cells using albumin clusters bearing ∼10 molecules of asparagine-linked glycans (N-glycans). Noninvasive near-infrared fluorescence imaging clearly revealed A431 tumors implanted in BALB/cA-nu/nu mice after 1h in an N-glycan structure-dependent manner, thereby demonstrating the efficient use of glycan multivalency effects for tumor targeting in vivo.

  May 2016, Bioorganic & medicinal chemistry letters, 26(9) (9), 2251 - 4, English, International magazine

  Scientific journal


• Exploration of Antiemetics for Osteoporosis Therapy-Induced Nausea and Vomiting Using PET Molecular Imaging Analysis to Gastrointestinal Pharmacokinetics

  Tomotaka Shingaki, Yumiko Katayama, Takayoshi Nakaoka, Tadayuki Takashima, Kayo Onoe, Takashi Okauchi, Emi Hayashinaka, Yasuhiro Wada, Yilong Cui, Yasuyoshi Watanabe

  May 2016, PHARMACEUTICAL RESEARCH, 33(5) (5), 1235 - 1248, English, International magazine

  [Refereed]

  Scientific journal


• Extension of recovery time from fatigue by repeated rest with short-term sleep during continuous fatigue load: Development of chronic fatigue model

  Akinori Kanzaki, Takashi Okauchi, Di Hu, Tomotaka Shingaki, Yumiko Katayama, Hidenori Koyama, Yasuyoshi Watanabe, Yilong Cui

  May 2016, JOURNAL OF NEUROSCIENCE RESEARCH, 94(5) (5), 424 - 429, English, International magazine

  [Refereed]

  Scientific journal


• Neural mechanisms to predict subjective level of fatigue in the future: a magnetoencephalography study.

  Akira Ishii, Masaaki Tanaka, Yasuyoshi Watanabe

  Fatigue is a major contributor to workplace accidents, morbidity, and mortality. To prevent the disruption of homeostasis and to concurrently accomplish an assigned workload, it is essential to control the level of workload based on the subjective estimation of the level of fatigue that will be experienced in the near future. In this study, we aimed to clarify the neural mechanisms related to predicting subjective levels of fatigue that would be experienced 60 min later, using magnetoencephalography. Sixteen healthy male volunteers participated in this study. In relation to the prediction, a decrease of alpha band power in the right Brodmann's area (BA) 40 and BA 9 at 1200 to 1350 ms and that in the right BA 9 at 1350 to 1500 ms, and a decrease of gamma band power in the right BA 10 at 1500 to 1650 ms were observed. In addition, the decreased level of alpha band power in BA 9 at 1200 to 1350 ms was positively associated with the daily level of fatigue. These findings may help increase our understanding of the neural mechanisms activated to indicate the need to take a rest based on the prediction of the subjective fatigue in the future.

  Apr. 2016, Scientific reports, 6, 25097 - 25097, English, International magazine

  Scientific journal


• ウロキナーゼ静脈内投与による樹状PEG修飾64Cuボンベシンアナログテトラマーのスイッチング型腎クリアランスを意図したPETプローブ

  向井 英史, 松村 一史, 造田 真希, 林中 恵美, 山下 富義, 橋田 充, 和田 康弘, 渡辺 恭良

  日本分子イメージング学会, Apr. 2016, JSMI Report, 9(2) (2), 130 - 130, Japanese

  [Refereed]


• 慢性疼痛モデルラットにおける線条体ドーパミンD2受容体の変容

  岡内 隆, 曾 瑩, 神母坂 あみ, 胡 迪, 林中 恵美, 和田 康弘, 土居 久志, 渡辺 恭良, 崔 翼龍

  日本分子イメージング学会, Apr. 2016, JSMI Report, 9(2) (2), 183 - 183, Japanese


• Visualization and Quantitative Assessment of the Brain Distribution of Insulin through Nose-to-Brain Delivery Based on the Cell-Penetrating Peptide Noncovalent Strategy.

  Noriyasu Kamei, Tomotaka Shingaki, Yousuke Kanayama, Misa Tanaka, Riyo Zochi, Koki Hasegawa, Yasuyoshi Watanabe, Mariko Takeda-Morishita

  Our recent work suggested that intranasal coadministration with the cell-penetrating peptide (CPP) penetratin increased the brain distribution of the peptide drug insulin. The present study aimed to distinctly certify the ability of penetratin to facilitate the nose-to-brain delivery of insulin by quantitatively evaluating the distribution characteristics in brain using radioactive (64)Cu-NODAGA-insulin. Autoradiography and analysis using a gamma counter of brain areas demonstrated that the accumulation of radioactivity was greatest in the olfactory bulb, the anterior part of the brain closest to the administration site, at 15 min after intranasal administration of (64)Cu-NODAGA-insulin with l- or d-penetratin. The brain accumulation of (64)Cu-NODAGA-insulin with penetratin was confirmed by ELISA using unlabeled insulin in which intact insulin was delivered to the brain after intranasal coadministration with l- or d-penetratin. By contrast, quantification of cerebrospinal fluid (CSF) samples showed increased insulin concentration in only the anterior portion of the CSF at 15 min after intranasal coadministration with l-penetratin. This study gives the first concrete proof that penetratin can accelerate the direct transport of insulin from the nasal cavity to the brain parenchyma. Further optimization of intranasal administration with CPP may increase the efficacy of delivery of biopharmaceuticals to the brain while reducing the risk of systemic drug exposure.

  Mar. 2016, Molecular pharmaceutics, 13(3) (3), 1004 - 11, English, International magazine

  Scientific journal


• イメージング技術が切り拓く遺伝子・核酸デリバリーの最前線 核酸創薬におけるポジトロンエミッショントモグラフィーの活用

  向井 英史, 渡辺 恭良

  (公社)日本薬学会, Mar. 2016, 日本薬学会年会要旨集, 136年会(1) (1), 286 - 286, Japanese


• Visualizing Trimming Dependence of Biodistribution and Kinetics with Homo- and Heterogeneous N-Glycoclusters on Fluorescent Albumin.

  Akihiro Ogura, Tsuyoshi Tahara, Satoshi Nozaki, Koji Morimoto, Yasuhiko Kizuka, Shinobu Kitazume, Mitsuko Hara, Soichi Kojima, Hirotaka Onoe, Almira Kurbangalieva, Naoyuki Taniguchi, Yasuyoshi Watanabe, Katsunori Tanaka

  A series of N-glycans, each sequentially trimmed from biantennary sialoglycans, were homo- or heterogeneously clustered efficiently on fluorescent albumin using a method that combined strain-promoted alkyne-azide cyclization and 6π-azaelectrocyclization. Noninvasive in vivo kinetics and dissection analysis revealed, for the first time, a glycan-dependent shift from urinary to gall bladder excretion mediated by sequential trimming of non-reducing end sialic acids. N-glycoalbumins that were trimmed further, in particular, GlcNAc- and hybrid biantennary-terminated congeners, were selectively taken up by sinusoidal endothelial and stellate cells in the liver, which are critical for diagnosis and treatment of liver fibrillation. Our glycocluster strategy can not only reveal the previously unexplored extracellular functions of N-glycan trimming, but will be classified as the newly emerging glycoprobes for diagnostic and therapeutic applications.

  Feb. 2016, Scientific reports, 6, 21797 - 21797, English, International magazine

  Scientific journal


• Detection of Cyclooxygenase-1 in Activated Microglia During Amyloid Plaque Progression: PET Studies in Alzheimer's Disease Model Mice.

  Miho Shukuri, Aya Mawatari, Masahiro Ohno, Masaaki Suzuki, Hisashi Doi, Yasuyoshi Watanabe, Hirotaka Onoe

  UNLABELLED: Cyclooxygenase (COX), a prostanoid-synthesizing enzyme, is considered to be involved in the neuroinflammatory process of neurodegenerative diseases. However, the role of COX in the progression of neurodegeneration is not well understood. We hypothesized that in vivo imaging of COX by PET will contribute to elucidation of the function of COX during the neurodegenerative process in Alzheimer's disease (AD). (11)C-labeled ketoprofen methyl ester (racemic (RS)-(11)C-KTP-Me) developed recently by our group is a useful PET probe for in vivo imaging of COX-1 during neuroinflammation. The (S)-enantiomer of ketoprofen is known to be pharmacologically more active than the (R)-enantiomer. We thus synthesized (11)C-labeled (S)-ketoprofen methyl ester ((S)-(11)C-KTP-Me) as an improved PET probe specific for COX-1 and applied it for investigation of the changes in COX-1 during the progression of AD in a mouse model. METHODS: The specificity of (S)-(11)C-KTP-Me for COXs was examined in PET studies with rats that had intrastriatal injection of lipopolysaccharide. To determine the details of changes in COX-1 during progression of amyloid-β (Aβ) plaque formation in amyloid precursor protein transgenic (APP-Tg) mice, we performed immunohistochemical studies and ex vivo autoradiography with (S)-(11)C-KTP-Me. RESULTS: PET studies using hemispheric lipopolysaccharide injection into rats revealed that the sensitivity of (S)-(11)C-KTP-Me in neuroinflammation was much higher than that of (RS)-(11)C-KTP-Me and (R)-(11)C-KTP-Me; these results closely corresponded to the inhibitory activities of each enantiomer against COX-1 estimated by an in vitro assay. In APP-Tg mice, (S)-(11)C-KTP-Me administration resulted in progressive and significant increases in accumulation of radioactivity in the brain from 16 to 24 mo old in accordance with the histopathologic appearance of abundant Aβ plaques and activated microglia, whereas few changes in radioactivity accumulation and few Aβ plaques were seen in age-matched wild-type control mice. High-radioactivity accumulation by (S)-(11)C-KTP-Me was markedly observed in the frontal cortex and hippocampus in which COX-1-expressing activated microglia tightly surrounded and enclosed large and more intensely stained Aβ plaques, indicating neuroinflammation that originated with Aβ. CONCLUSION: (S)-(11)C-KTP-Me is a potent PET probe that is highly selective for COX-1. Studies using APP-Tg mice demonstrated that (S)-(11)C-KTP-Me could detect activated microglia that are associated with amyloid plaque progression, suggesting the involvement of COX-1 in the neuroinflammatory process in AD.

  Feb. 2016, Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 57(2) (2), 291 - 6, English, International magazine

  Scientific journal


• Visualization of drug translocation in the nasal cavity and pharmacokinetic analysis on nasal drug absorption using positron emission tomography in the rat

  Tomotaka Shingaki, Yumiko Katayama, Takayoshi Nakaoka, Satsuki Irie, Kayo Onoe, Takashi Okauchi, Emi Hayashinaka, Masataka Yamaguchi, Nobuyoshi Tanki, Takayuki Ose, Takuya Hayashi, Yasuhiro Wada, Tomoyuki Furubayashi, Yilong Cui, Toshiyasu Sakane, Yasuyoshi Watanabe

  Feb. 2016, EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, 99, 45 - 53, English, International magazine

  [Refereed]

  Scientific journal


• Molecular imaging using PET for breast cancer.

  Hiroaki Kurihara, Chikako Shimizu, Yasuji Miyakita, Masayuki Yoshida, Akinobu Hamada, Yousuke Kanayama, Kan Yonemori, Jun Hashimoto, Hitomi Tani, Makoto Kodaira, Mayu Yunokawa, Harukaze Yamamoto, Yasuyoshi Watanabe, Yasuhiro Fujiwara, Kenji Tamura

  Molecular imaging can visualize the biological processes at the molecular and cellular levels in vivo using certain tracers for specific molecular targets. Molecular imaging of breast cancer can be performed with various imaging modalities, however, positron emission tomography (PET) is a sensitive and non-invasive molecular imaging technology and this review will focus on PET molecular imaging of breast cancer, such as FDG-PET, FLT-PET, hormone receptor PET, and anti-HER2 PET.

  Jan. 2016, Breast cancer (Tokyo, Japan), 23(1) (1), 24 - 32, English, Domestic magazine

  Scientific journal


• Low putamen activity associated with poor reward sensitivity in childhood chronic fatigue syndrome.

  Kei Mizuno, Junko Kawatani, Kanako Tajima, Akihiro T Sasaki, Tetsuya Yoneda, Masanori Komi, Toshinori Hirai, Akemi Tomoda, Takako Joudoi, Yasuyoshi Watanabe

  Motivational signals influence a wide variety of cognitive processes and components of behavioral performance. Cognitive dysfunction in patients with childhood chronic fatigue syndrome (CCFS) may be closely associated with a low motivation to learn induced by impaired neural reward processing. However, the extent to which reward processing is impaired in CCFS patients is unclear. The aim of the present functional magnetic resonance imaging (fMRI) study was to determine whether brain activity in regions related to reward sensitivity is impaired in CCFS patients. fMRI data were collected from 13 CCFS patients (mean age, 13.6 ± 1.0 years) and 13 healthy children and adolescents (HCA) (mean age, 13.7 ± 1.3 years) performing a monetary reward task. Neural activity in high- and low-monetary-reward conditions was compared between CCFS and HCA groups. Severity of fatigue and the reward obtained from learning in daily life were evaluated by questionnaires. Activity of the putamen was lower in the CCFS group than in the HCA group in the low-reward condition, but not in the high-reward condition. Activity of the putamen in the low-reward condition in CCFS patients was negatively and positively correlated with severity of fatigue and the reward from learning in daily life, respectively. We previously revealed that motivation to learn was correlated with striatal activity, particularly the neural activity in the putamen. This suggests that in CCFS patients low putamen activity, associated with altered dopaminergic function, decreases reward sensitivity and lowers motivation to learn.

  2016, NeuroImage. Clinical, 12, 600 - 606, English, International magazine

  Scientific journal


• Ni/Cu-Catalyzed Defluoroborylation of Fluoroarenes for Diverse C-F Bond Functionalizations.

  Takashi Niwa, Hidenori Ochiai, Yasuyoshi Watanabe, Takamitsu Hosoya

  Ni/Cu-catalyzed transformation of fluoroarenes to arylboronic acid pinacol esters via C-F bond cleavage has been achieved. Further versatile derivatization of an arylboronic ester has allowed for the facile two-step conversion of a fluoroarene to diverse functionalized arenes, demonstrating the synthetic utility of the method.

  Nov. 2015, Journal of the American Chemical Society, 137(45) (45), 14313 - 8, English, International magazine

  Scientific journal


• Physical fatigue increases neural activation during eyes-closed state: a magnetoencephalography study.

  Masaaki Tanaka, Akira Ishii, Yasuyoshi Watanabe

  BACKGROUND: Fatigue, defined as difficulty initiating or sustaining voluntary activities, can be classified as physical or mental. In this study, we use magnetoencephalography (MEG) to quantify the effect of physical fatigue on neural activity under the condition of simulated physical load. METHODS: Thirteen healthy right-handed male volunteers participated in this study. The experiment consisted of one fatigue-inducing physical task session performed between two MEG sessions. During the 10-min physical task session, participants performed maximum-effort handgrips with the left hand lasting 1 s every 4 s; during MEG sessions, 3-min recordings were made during the eyes-closed state. MEG data were analyzed using narrow-band adaptive spatial filtering methods. RESULTS: Alpha-frequency band (8-13 Hz) power in the left postcentral gyrus, precentral gyrus, and middle frontal gyrus (Brodmann's areas 1, 2, 3, 4, 6, and 46) were decreased after performing the physical fatigue-inducing task. CONCLUSIONS: These results show that performing the physical fatigue-inducing task caused activation of the left sensorimotor and prefrontal areas, manifested as decreased alpha-frequency band power in these brain areas. Our results increase understanding of the neural mechanisms of physical fatigue.

  Nov. 2015, Behavioral and brain functions : BBF, 11(1) (1), 35 - 35, English, International magazine

  Scientific journal


• Frontier studies on fatigue, autonomic nerve dysfunction, and sleep-rhythm disorder.

  Masaaki Tanaka, Seiki Tajima, Kei Mizuno, Akira Ishii, Yukuo Konishi, Teruhisa Miike, Yasuyoshi Watanabe

  Fatigue is defined as a condition or phenomenon of decreased ability and efficiency of mental and/or physical activities, caused by excessive mental or physical activities, diseases, or syndromes. It is often accompanied by a peculiar sense of discomfort, a desire to rest, and reduced motivation, referred to as fatigue sensation. Acute fatigue is a normal condition or phenomenon that disappears after a period of rest; in contrast, chronic fatigue, lasting at least 6 months, does not disappear after ordinary rest. Chronic fatigue impairs activities and contributes to various medical conditions, such as cardiovascular disease, epileptic seizures, and death. In addition, many people complain of chronic fatigue. For example, in Japan, more than one third of the general adult population complains of chronic fatigue. It would thus be of great value to clarify the mechanisms underlying chronic fatigue and to develop efficient treatment methods to overcome it. Here, we review data primarily from behavioral, electrophysiological, and neuroimaging experiments related to neural dysfunction as well as autonomic nervous system, sleep, and circadian rhythm disorders in fatigue. These data provide new perspectives on the mechanisms underlying chronic fatigue and on overcoming it.

  Nov. 2015, The journal of physiological sciences : JPS, 65(6) (6), 483 - 98, English, Domestic magazine

  Scientific journal


• Impaired neural reward processing in children and adolescents with reactive attachment disorder: A pilot study.

  Kei Mizuno, Shinichiro Takiguchi, Mika Yamazaki, Mizuki Asano, Shiho Kato, Kikuko Kuriyama, Yasuyoshi Watanabe, Norihiro Sadato, Akemi Tomoda

  Reactive attachment disorder (RAD) is characterized by markedly disturbed and developmentally inappropriate social relatedness due to parental maltreatment. RAD patients often display a high number of comorbid attention deficit/hyperactivity disorder (ADHD) symptoms, and certain RAD symptoms are difficult to discriminate from ADHD. One of the core characteristics of ADHD is a decrease in neural reward processing due to dopamine dysfunction. The aim of the present study was to determine whether the brain activity involved in reward processing in RAD patients is impaired in comparison with ADHD patients and typically developed controls. Five RAD patients, 17 typically developed (TD) controls and 17 ADHD patients aged 10-16 years performed tasks with high and low monetary reward while undergoing functional magnetic resonance imaging. ADHD patients were tested before and after 3 months treatment with osmotic release oral system-methylphenidate. Before treatment, ADHD patients showed that striatal and thalamus activities only in the tasks with low monetary reward were lower than TD controls. RAD patients showed decrease in activity of the caudate, putamen and thalamus during both the high and low monetary reward conditions in comparison with all the other groups. In RAD patients, the activity of the putamen was associated with the severity of posttraumatic stress and overt dissociation. Reward sensitivity was markedly decreased in children and adolescents with RAD, as evidenced by a diminished neural response during reward perception. This suggests that dopaminergic dysfunction exists in these patients, and may inform future dopaminergic treatment strategies for RAD.

  Oct. 2015, Asian journal of psychiatry, 17, 89 - 93, English, International magazine

  Scientific journal


• Regional brain disorders of serotonin neurotransmission are associated with functional dyspepsia.

  Kazunari Tominaga, Chikako Tsumoto, Suzuka Ataka, Kei Mizuno, Kayo Takahashi, Hirokazu Yamagami, Tetsuya Tanigawa, Joji Kawabe, Toshio Watanabe, Yasuhiro Fujiwara, Susumu Shiomi, Yasuyoshi Watanabe, Tetsuo Arakawa

  AIMS: To elucidate the role of cerebral serotonin neurotransmission in visceral perception in functional dyspepsia (FD), we observationally examined the regional expression level of the serotonin transporter (SERT) and its correlation with clinical symptoms. MAIN METHODS: FD patients (Rome III criteria; N=9, age range: 36-76years) and healthy controls (N=8, age range: 25-61years) participated in this study. Positron emission tomography scanning with [(11)C]N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine ([(11)C]DASB), which binds specifically to SERT, was used to quantify the binding potential (BPND) of [(11)C]DASB in the midbrain, thalamus, caudate, putamen, amygdala, and hippocampus with reference to co-registered magnetic resonance images. Clinical symptoms were assessed using the Gastrointestinal Symptoms Rating Scale (GSRS). Self-Rating Depression Scale (SDS), and State-Trait Anxiety Inventory (STAI). KEY FINDINGS: BPND of the midbrain (P=0.041) and thalamus (P=0.031) was higher in FD patients than in controls. The BPND values in the midbrain correlated with total GSRS (r=0.663, P=0.004) and abdominal pain (r=0.419, P=0.047) scores. Its values in the thalamus correlated with total GSRS (r=0.423, P=0.044), abdominal pain (r=0.502, P=0.022), and indigestion (r=0.476, P=0.028) scores. Its value in the hippocampus correlated with abdominal pain and state-STAI scores (r=0.528, P=0.017; r=0.428, P=0.043). SIGNIFICANCE: Up-regulation of the SERT level in the midbrain and thalamus may underlie the pathogenesis of FD such as abdominal and psychological symptoms via a brain-gut interaction.

  Sep. 2015, Life sciences, 137, 150 - 7, English, International magazine

  Scientific journal


• 高齢者タウオパチーを疑う認知症患者のPBB3-PETタウイメージング

  竹内 潤, 安宅 鈴香, 島田 斉, 樋口 真人, 和田 康弘, 塩見 進, 渡辺 恭良, 須原 哲也, 嶋田 裕之, 伊藤 義彰

  (一社)日本認知症学会, Sep. 2015, Dementia Japan, 29(3) (3), 387 - 387, Japanese


• Quantitative Evaluation of mMate1 Function Based on Minimally Invasive Measurement of Tissue Concentration Using PET with [C-11] Metformin in Mouse

  Tomotaka Shingaki, W. Ewan Hume, Tadayuki Takashima, Yumiko Katayama, Takashi Okauchi, Emi Hayashinaka, Yasuhiro Wada, Yilong Cui, Hiroyuki Kusuhara, Yuichi Sugiyama, Yasuyoshi Watanabe

  Aug. 2015, PHARMACEUTICAL RESEARCH, 32(8) (8), 2538 - 2547, English, International magazine

  [Refereed]

  Scientific journal


• 病態解明のための生体機能イメージング法の新展開 PETを中心とした分子イメージングによる個体レベルでの病態解明と診断・創薬への展開

  向井 英史, 渡辺 恭良

  (公社)日本分析化学会, Aug. 2015, 日本分析化学会講演要旨集, 64年会, 5 - 5, Japanese


• Synthesis of (11)C-Labeled Thiamine and Fursultiamine for in Vivo Molecular Imaging of Vitamin B1 and Its Prodrug Using Positron Emission Tomography.

  Hisashi Doi, Aya Mawatari, Masakatsu Kanazawa, Satoshi Nozaki, Yukihiro Nomura, Takahito Kitayoshi, Kouji Akimoto, Masaaki Suzuki, Shinji Ninomiya, Yasuyoshi Watanabe

  To enable in vivo analysis of the kinetics of vitamin B1 (thiamine) and its derivatives by positron emission tomography (PET), (11)C-labeled thiamine ([(11)C]-1) has been synthesized. This was carried out via a rapid, multistep synthesis consisting of Pd(0)-mediated C-[(11)C]methylation of a thiazole ring for 3 min and benzylation with 5-(bromomethyl)pyrimidine for 7 min. The [(11)C]-1 was also converted to (11)C-labeled fursultiamine ([(11)C]-2), a prodrug of vitamin B1, by disulfide formation with S-tetrahydrofurfurylthiosulfuric acid sodium salt. Characterization of [(11)C]-1 and [(11)C]-2 showed them to be suitable for use as PET probes for in vivo pharmacokinetic and medical studies. The total durations of the preparations of [(11)C]-1 and [(11)C]-2 were shorter than 60 and 70 min, respectively. The [(11)C]CH3I-based decay-corrected radiochemical yields of [(11)C]-1 and [(11)C]-2 were 9-16% and 4-10%, respectively. The radioactivities of the final injectable solutions of [(11)C]-1 and [(11)C]-2 were 400-700 and 100-250 MBq, respectively. The radiochemical purity of both [(11)C]-1 and [(11)C]-2 was 99%, and the chemical purities of [(11)C]-1 and [(11)C]-2 were 99% and 97-99%, respectively. In vivo PET imaging of normal rats was illustrated by the distribution of [(11)C]-1 and [(11)C]-2 following intravenous injection.

  Jun. 2015, The Journal of organic chemistry, 80(12) (12), 6250 - 8, English, International magazine

  Scientific journal


• 生理条件下代謝開裂部位導入による64Cu標識ボンベシンアナログテトラマーを用いた癌PETイメージングの画像コントラスト改善

  松村 一史, 向井 英史, 造田 真希, 高橋 麻衣子, 林中 恵美, 山下 富義, 橋田 充, 和田 康弘, 渡辺 恭良

  日本DDS学会, Jun. 2015, 日本DDS学会学術集会プログラム予稿集, 31回, 140 - 140, Japanese

  [Refereed]


• 神経・内分泌・免疫機能の破綻を伴う新たな慢性疲労モデルの確立

  神崎 暁慶, 崔 翼龍, 片山 由美子, 岡内 隆, 胡 迪, 新垣 友隆, 小山 英則, 渡辺 恭良

  日本疲労学会, May 2015, 日本疲労学会誌, 11(1) (1), 66 - 66, Japanese


• Fatigue and sleep under large summer temperature differences.

  Hisako Fujii, Sanae Fukuda, Daisuke Narumi, Tomohiko Ihara, Yasuyoshi Watanabe

  BACKGROUND: It has been recognized that an increase in outdoor ambient temperatures has a negative impact on health, particularly fatigue and sleep quality; however, the relationship among fatigue, sleep quality, and air temperature has yet to be sufficiently elucidated. OBJECTIVES: To examine whether fatigue and sleep quality in a healthy Japanese population were affected by rising air temperature at three time points in summer and to investigate the confounding factors for fatigue. METHODS: A total of 602 healthy volunteers in Osaka, Japan, participated in a survey that was conducted at the end of July, August, and September in 2010. The questionnaire consisted of four sections; demographic variables, accommodation status, fatigue, and sleep quality. We used the Chalder fatigue scale for assessment of fatigue, and the Japanese version of the Pittsburgh Sleep Quality Index (PSQI) for assessment of sleep quality. RESULTS: The fatigue score was positively correlated with the sleep quality score in the total cohort. All the questionnaires at the three time points were completed by 162 participants. There were significant differences in fatigue scores among the surveys. We stratified the subjects into two groups of good and poor sleepers using a cutoff value of the PSQI. The good sleepers did not show differences in fatigue score regardless of the change in air temperature. However, the fatigue score of poor sleepers was greater at higher air temperatures. The use of air conditioners, accommodation type, and subject's age were confounding factors for fatigue. CONCLUSIONS: High air temperatures in summer increased fatigue in healthy volunteers, especially those with poor sleep patterns, depending on the use of air conditioners, accommodation status, and subject's age.

  Apr. 2015, Environmental research, 138, 17 - 21, English, International magazine

  Scientific journal


• 創薬と臨床開発の新時代を見据えたPETによる医薬品候補化合物の薬物動態評価

  新垣 友隆, 崔 翼龍, 渡辺 恭良

  日本医学会, Apr. 2015, 日本医学会総会会誌, 29回(学術講演要旨) (学術講演要旨), 68 - 68, Japanese


• A voxel-based analysis of brain activity in high-order trigeminal pathway in the rat induced by cortical spreading depression

  Yilong Cui, Hiroshi Toyoda, Takeo Sako, Kayo Onoe, Emi Hayashinaka, Yasuhiro Wada, Chihiro Yokoyama, Hirotaka Onoe, Yosky Kataoka, Yasuyoshi Watanabe

  Mar. 2015, NEUROIMAGE, 108, 17 - 22, English, International magazine

  [Refereed]

  Scientific journal


• Potential Biomarkers of Fatigue Identified by Plasma Metabolome Analysis in Rats

  Satoshi Kume, Masanori Yamato, Yasuhisa Tamura, Guanghua Jin, Masayuki Nakano, Yukiharu Miyashige, Asami Eguchi, Yoshiyuki Ogata, Nobuhito Goda, Kazuhiro Iwai, Emi Yamano, Yasuyoshi Watanabe, Tomoyoshi Soga, Yosky Kataoka

  Mar. 2015, PLOS ONE, 10(3) (3), e0120106, English, International magazine

  [Refereed]

  Scientific journal


• 脳標的化薬物デリバリー研究の最前線 PETを用いた鼻腔内投与後の薬物動態と直接的脳移行の可視化

  新垣 友隆, 古林 呂之, 坂根 稔康, 崔 翼龍, 渡辺 恭良

  (公社)日本薬学会, Mar. 2015, 日本薬学会年会要旨集, 135年会(1) (1), 198 - 198, Japanese


• Development of a Body Shield for Small Animal PET System to Reduce Random and Scatter Coincidences

  Yasuhiro Wada, Seiichi Yamamoto, Yasuyoshi Watanabe

  Feb. 2015, IEEE TRANSACTIONS ON NUCLEAR SCIENCE, 62(1) (1), 95 - 100, English

  [Refereed]

  Scientific journal


• 11C-Labeled Capsaicin and its in Vivo Molecular Imaging in Rats by Positron Emission Tomography

  Goto, M., Mizuma, H., Wada, Y., Suzuki, M., Watanabe, Y., Onoe, H., Doi, H.

  2015, Food and Nutrition Sciences, 6

  Scientific journal


• The neural mechanisms of re-experiencing mental fatigue sensation: a magnetoencephalography study.

  Akira Ishii, Takuma Karasuyama, Taiki Kikuchi, Masaaki Tanaka, Emi Yamano, Yasuyoshi Watanabe

  There have been several studies which have tried to clarify the neural mechanisms of fatigue sensation; however fatigue sensation has multiple aspects. We hypothesized that past experience related to fatigue sensation is an important factor which contributes to future formation of fatigue sensation through the transfer to memories that are located within specific brain structures. Therefore, we aimed to investigate the neural mechanisms of fatigue sensation related to memory. In the present study, we investigated the neural activity caused by re-experiencing the fatigue sensation that had been experienced during a fatigue-inducing session. Thirteen healthy volunteers participated in fatigue and non-fatigue experiments in a crossover fashion. In the fatigue experiment, they performed a 2-back test session for 40 min to induce fatigue sensation, a rest session for 15 min to recover from fatigue, and a magnetoencephalography (MEG) session in which they were asked to re-experience the state of their body with fatigue that they had experienced in the 2-back test session. In the non-fatigue experiment, the participants performed a free session for 15 min, a rest session for 15 min, and an MEG session in which they were asked to re-experience the state of their body without fatigue that they had experienced in the free session. Spatial filtering analyses of oscillatory brain activity showed that the delta band power in the left Brodmann's area (BA) 39, alpha band power in the right pulvinar nucleus and the left BA 40, and beta band power in the left BA 40 were lower when they re-experienced the fatigue sensation than when they re-experienced the fatigue-free sensation, indicating that these brain regions are related to re-experiencing the fatigue sensation. Our findings may help clarify the neural mechanisms underlying fatigue sensation.

  2015, PloS one, 10(3) (3), e0122455, English, International magazine

  Scientific journal


• (64)Cu-DOTA-trastuzumab PET imaging and HER2 specificity of brain metastases in HER2-positive breast cancer patients.

  Hiroaki Kurihara, Akinobu Hamada, Masayuki Yoshida, Schuichi Shimma, Jun Hashimoto, Kan Yonemori, Hitomi Tani, Yasuji Miyakita, Yousuke Kanayama, Yasuhiro Wada, Makoto Kodaira, Mayu Yunokawa, Harukaze Yamamoto, Chikako Shimizu, Kazuhiro Takahashi, Yasuyoshi Watanabe, Yasuhiro Fujiwara, Kenji Tamura

  BACKGROUND: The purpose of this study was to determine whether brain metastases from HER2-positive breast cancer could be detected noninvasively using positron emission tomography (PET) with (64)Cu-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-trastuzumab. METHODS: PET was performed on five patients with brain metastases from HER2-positive breast cancer, at 24 or 48 h after the injection of approximately 130 MBq of the probe (64)Cu-DOTA-trastuzumab. Radioactivity in metastatic brain tumors was evaluated based on PET images in five patients. Autoradiography, immunohistochemistry (IHC), and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis were performed in one surgical case to confirm HER2 specificity of (64)Cu-DOTA-trastuzumab. RESULTS: Metastatic brain lesions could be visualized by (64)Cu-DOTA-trastuzumab PET in all of five cases, which might indicated that trastuzumab passes through the blood-brain barrier (BBB). The HER2 specificity of (64)Cu-DOTA-trastuzumab was demonstrated in one patient by autoradiography, immunohistochemistry, and LC-MS/MS. CONCLUSIONS: Cu-DOTA-trastuzumab PET could be a potential noninvasive procedure for serial identification of metastatic brain lesions in patients with HER2-positive breast cancer. TRIAL REGISTRATION: UMIN000004170.

  2015, EJNMMI research, 5, 8 - 8, English, International magazine

  Scientific journal


• Imaging the passionate stage of romantic love by dopamine dynamics.

  Kayo Takahashi, Kei Mizuno, Akihiro T Sasaki, Yasuhiro Wada, Masaaki Tanaka, Akira Ishii, Kanako Tajima, Naohiro Tsuyuguchi, Kyosuke Watanabe, Semir Zeki, Yasuyoshi Watanabe

  Using [(11)C]raclopride, a dopamine D2/D3 receptor antagonist, we undertook a positron emission tomography (PET) study to investigate the involvement of the dopaminergic neurotransmitter system when subjects viewed the pictures of partners to whom they were romantically attached. Ten subjects viewed pictures of their romantic partners and, as a control, of friends of the same sex for whom they had neutral feelings during the PET study. We administered [(11)C]raclopride to subjects using a timing for injecting the antagonist which had been determined in previous studies to be optimal for detecting increases in the amount of dopamine released by stimulation. The results demonstrated statistically significant activation of the dopaminergic system in two regions, the medial orbitofrontal cortex (mOFC) and medial prefrontal cortex, the former of which has been strongly implicated in a variety of rewarding experiences, including that of beauty and love. A positive correlation was obtained in mOFC between excitement levels and dopaminergic activation only in the love but not in the control condition.

  2015, Frontiers in human neuroscience, 9, 191 - 191, English, International magazine

  Scientific journal


• Less efficient and costly processes of frontal cortex in childhood chronic fatigue syndrome.

  Kei Mizuno, Masaaki Tanaka, Hiroki C Tanabe, Takako Joudoi, Junko Kawatani, Yoshihito Shigihara, Akemi Tomoda, Teruhisa Miike, Kyoko Imai-Matsumura, Norihiro Sadato, Yasuyoshi Watanabe

  The ability to divide one's attention deteriorates in patients with childhood chronic fatigue syndrome (CCFS). We conducted a study using a dual verbal task to assess allocation of attentional resources to two simultaneous activities (picking out vowels and reading for story comprehension) and functional magnetic resonance imaging. Patients exhibited a much larger area of activation, recruiting additional frontal areas. The right middle frontal gyrus (MFG), which is included in the dorsolateral prefrontal cortex, of CCFS patients was specifically activated in both the single and dual tasks; this activation level was positively correlated with motivation scores for the tasks and accuracy of story comprehension. In addition, in patients, the dorsal anterior cingulate gyrus (dACC) and left MFG were activated only in the dual task, and activation levels of the dACC and left MFG were positively associated with the motivation and fatigue scores, respectively. Patients with CCFS exhibited a wider area of activated frontal regions related to attentional resources in order to increase their poorer task performance with massive mental effort. This is likely to be less efficient and costly in terms of energy requirements. It seems to be related to the pathophysiology of patients with CCFS and to cause a vicious cycle of further increases in fatigue.

  2015, NeuroImage. Clinical, 9, 355 - 68, English, International magazine

  Scientific journal


• 【DDS研究30年:温故知新】(第7章)バイオイメージング技術 PET分子イメージング活用創薬

  渡辺 恭良, 向井 英史, 新垣 友隆

  (株)じほう, Jan. 2015, PHARM TECH JAPAN, 31(2) (2), 442 - 447, Japanese

  [Refereed]

  Scientific journal


• Effects of nutritional supplementation on fatigue, and autonomic and immune dysfunction in patients with end-stage renal disease: a randomized, double-blind, placebo-controlled, multicenter trial.

  Fukuda S, Koyama H, Kondo K, Fujii H, Hirayama Y, Tabata T, Okamura M, Yamakawa T, Okada S, Hirata S, Kiyama H, Kajimoto O, Watanabe Y, Inaba M, Nishizawa Y

  BACKGROUND: Fatigue is a predictor of cardiovascular events in patients with end-stage renal disease (ESRD) undergoing hemodialysis treatment. We hypothesized that multinutritional support would improve quality of life, fatigue symptoms, and potential quantitative measures including endocrine, immune and autonomic functions in patients with ESRD undergoing hemodialysis. METHODS: Two hundred and two hemodialysis patients were randomly assigned to receive active treatment (containing vitamin B1, vitamin B2, niacin, vitamin B6, vitamin B12, folic acid, vitamin C, carnitine, coenzyme Q10, naïve galacto-oligosaccharide, and zinc) or placebo after each dialysis session for 12 weeks. The patients and attending physicians were blinded to the treatment, and 172 patients (86 in each group) completed the study. Fatigue was evaluated via fatigue questionnaire at 0, 4, and 12 weeks. To assess human herpes virus (HHV) 6 and 7 reactivation, numbers of viral DNA copies were determined in saliva by polymerase chain reaction at weeks 0 and 12. Autonomic function was determined via measurement of beat-to-beat variation by using acceleration plethysmography. RESULTS: Clinical characteristics, changes in fatigue, quality of life score, endocrine functions, and laboratory data did not differ significantly between the two groups. Several parameters of heart rate variability significantly increased after nutritional treatment compared to placebo. Nutritional drink for 12 weeks significantly suppressed HHV7 DNA copy numbers. Similarly, HHV6 DNA copy numbers tended to be decreased by treatment but without reaching statistical significance. CONCLUSIONS: Nutritional supplementation may modulate immune and autonomic dysfunction in ESRD patients undergoing hemodialysis.

  2015, PloS one, 10(3) (3), e0119578, English, International magazine

  [Refereed]

  Scientific journal


• Role of cortical spreading depression in the pathophysiology of migraine.

  Yilong Cui, Yosky Kataoka, Yasuyoshi Watanabe

  A migraine is a recurring neurological disorder characterized by unilateral, intense, and pulsatile headaches. In one-third of migraine patients, the attacks are preceded by a visual aura, such as a slowly-propagating scintillating scotoma. Migraine aura is thought to be a result of the neurovascular phenomenon of cortical spreading depression (SD), a self-propagating wave of depolarization that spreads across the cerebral cortex. Several animal experiments have demonstrated that cortical SD causes intracranial neurogenic inflammation around the meningeal blood vessels, such as plasma protein extravasation and pro-inflammatory peptide release. Cortical SD has also been reported to activate both peripheral and central trigeminal nociceptive pathways. Although several issues remain to be resolved, recent evidence suggests that cortical SD could be the initial trigger of intracranial neurogenic inflammation, which then contributes to migraine headaches via subsequent activation of trigeminal afferents.

  Oct. 2014, Neuroscience bulletin, 30(5) (5), 812 - 22, English, International magazine

  Scientific journal


• Human whole-body biodistribution and dosimetry of a new PET tracer, [(11)C]ketoprofen methyl ester, for imagings of neuroinflammation.

  Akihito Ohnishi, Michio Senda, Tomohiko Yamane, Masahiro Sasaki, Tomoko Mikami, Tomoyuki Nishio, Yasuhiko Ikari, Hiroyuki Nishida, Miho Shukuri, Tadayuki Takashima, Aya Mawatari, Hisashi Doi, Yasuyoshi Watanabe, Hirotaka Onoe

  INTRODUCTION: Neuroinflammatory processes play an important role in the pathogenesis of Alzheimer's disease and other brain disorders, and nonsteroidal anti-inflammatory drugs (NSAIDs) are considered therapeutic candidates. As a biomarker of neuroinflammatory processes, (11)C-labeled ketoprofen methyl ester ([(11)C]KTP-Me) was designed to allow cerebral penetration of ketoprofen (KTP), an active form of a selective cyclooxygenase-1 inhibitor that acts as an NSAID. Rat neuroinflammation models indicate that [(11)C]KTP-Me enters the brain and is retained in inflammatory lesions, accumulating in activated microglia. [(11)C]KTP-Me is washed out from normal tissues, leading to the present first-in-human exploratory study. METHODS: [(11)C]KTP-Me was synthesized by rapid C-[(11)C]methylation of [(11)C]CH3I and the corresponding arylacetate precursor, purified with high-performance liquid chromatography, and prepared as an injectable solution including PEG400, providing radiochemical purity of >99% and specific activity of >25GBq/μmol at injection. Six young healthy male humans were injected with [(11)C]KTP-Me and scanned with PET camera to determine the early-phase brain time course followed by three whole-body scans starting 8, 20, and 40 min post-injection, together with sequential blood sampling and labeled metabolite analysis. RESULTS: No adverse effects were observed during PET scanning after [(11)C]KTP-Me injection. [(11)C]KTP-Me was rapidly metabolized to (11)C-labeled ketoprofen ([(11)C]KTP) within 2-3 min and was gradually cleared from blood. The radioactivity entered the brain with an average peak cortical SUV of 1.5 at 2 min. The cortical activity was gradually washed out. Whole-body images indicated that the urinary bladder was the major excretory pathway. The organ with the highest radiation dose was the urinary bladder (average dose of 41μGy/MBq, respectively). The mean effective dose was 4.7μSv/MBq, which was comparable to other (11)C-labeled radiopharmaceuticals. CONCLUSION: [(11)C]KTP-Me demonstrated a favorable dosimetry, biodistribution, and safety profile. [(11)C]KTP-Me entered the human brain, and the radioactivity was washed out from cerebral tissue. These data warrant further exploratory studies on patients with neuroinflammation.

  Aug. 2014, Nuclear medicine and biology, 41(7) (7), 594 - 9, English, International magazine

  Scientific journal


• Fatigue correlates with the decrease in parasympathetic sinus modulation induced by a cognitive challenge.

  Kei Mizuno, Kanako Tajima, Yasuyoshi Watanabe, Hirohiko Kuratsune

  BACKGROUND: It is known that enhancement of sympathetic nerve activity based on a decrease in parasympathetic nerve activity is associated with fatigue induced by mental tasks lasting more than 30 min. However, to measure autonomic nerve function and assess fatigue levels in both clinical and industrial settings, shorter experimental durations and more sensitive measurement methods are needed. The aim of the present study was to establish an improved method for inducing fatigue and evaluating the association between it and autonomic nerve activity. METHODS: Twenty-eight healthy female college students participated in the study. We used a kana pick-out test (KPT) as a brief verbal cognitive task and recorded electrocardiography (ECG) to measure autonomic nerve activity. The experimental design consisted of a 16-min period of ECG: A pre-task resting state with eyes open for 3 min and eyes closed for 3 min, the 4-min KPT, and a post-task resting state with eyes open for 3 min and eyes closed for 3 min. RESULTS: Baseline fatigue sensation, measured by a visual analogue scale before the experiment, was associated with the decrease in parasympathetic sinus modulation, as indicated the by ratio of low-frequency component power (LF) to high-frequency component power (HF), during the KPT. The LF/HF ratio during the post-KPT rest with eyes open tended to be greater than the ratio during the KPT and correlated with fatigue sensation. Fatigue sensation was correlated negatively with log-transformed HF, which is an index of parasympathetic sinus modulation, during the post-KPT rest with eyes open. CONCLUSIONS: The methods described here are useful for assessing the association between fatigue sensation and autonomic nerve activity using a brief cognitive test in healthy females.

  Jul. 2014, Behavioral and brain functions : BBF, 10, 25 - 25, English, International magazine

  Scientific journal


• Validation of threshold method for myocardial control database by use of clinical data.

  Atsushi Narita, Susumu Shiomi, Joji Kawabe, Hiroyuki Tsushima, Takashi Yamanaga, Yasuyoshi Watanabe

  A database is an important factor in the statistical analysis of myocardial scintigraphy. Our aim in this study was to verify the validity of the threshold method using phantoms and to create a clinical database using this method. Since this method involves artificially excluding a low count area on a polar map, we created a myocardial phantom with defects. Then, we applied this method to the construction of a control database (CDB) for which we used stress-rest scans of 152 male and 52 female Japanese patients. The clinical relevance of this database was investigated by comparison of the values between the CDB and a Japanese normal database. In the study evaluation, we mainly used the summed extent score (SES) and a severity map (severity). Data from the phantom with defects demonstrated that the threshold method could compensate for defective areas, enabling the use of data for the creation of the CDB. Comparison of the CDB with the Japanese normal database showed a good relationship with respect to the SES and severity (Initial post-stress: SES: r = 0.978; severity: r = 0.997, Redistribution: SES: r = 0.944; severity: r = 0.993). The threshold method facilitates the effective creation of a database by use of clinical data. This enables individual institutions to build their own databases, taking into account differences in collection and processing conditions between institutions as well as the characteristics of individual equipment.

  Jul. 2014, Radiological physics and technology, 7(2) (2), 340 - 51, English, Domestic magazine

  Scientific journal


• Efficient syntheses of [¹¹C]zidovudine and its analogs by convenient one-pot palladium(0)-copper(I) co-mediated rapid C-[¹¹C]methylation.

  Zhouen Zhang, Hisashi Doi, Hiroko Koyama, Yasuyoshi Watanabe, Masaaki Suzuki

  Jun. 2014, Journal of labelled compounds & radiopharmaceuticals, 57(8) (8), 540 - 9, English, International magazine

  Scientific journal


• Suppressive responses by visual food cues in postprandial activities of insular cortex as revealed by magnetoencephalography.

  Takahiro Yoshikawa, Masaaki Tanaka, Akira Ishii, Yasuyoshi Watanabe

  Jun. 2014, Brain research, 1568, 31 - 41, English, International magazine

  Scientific journal


• Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An ¹¹C-(R)-PK11195 PET Study.

  Yasuhito Nakatomi, Kei Mizuno, Akira Ishii, Yasuhiro Wada, Masaaki Tanaka, Shusaku Tazawa, Kayo Onoe, Sanae Fukuda, Joji Kawabe, Kazuhiro Takahashi, Yosky Kataoka, Susumu Shiomi, Kouzi Yamaguti, Masaaki Inaba, Hirohiko Kuratsune, Yasuyoshi Watanabe

  UNLABELLED: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a disease characterized by chronic, profound, disabling, and unexplained fatigue. Although it is hypothesized that brain inflammation is involved in the pathophysiology of CFS/ME, there is no direct evidence of neuroinflammation in patients with CFS/ME. Activation of microglia or astrocytes is related to neuroinflammation. (11)C-(R)-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carboxamide ((11)C-(R)-PK11195) is a ligand of PET for a translocator protein that is expressed by activated microglia or astrocytes. We used (11)C-(R)-PK11195 and PET to investigate the existence of neuroinflammation in CFS/ME patients. METHODS: Nine CFS/ME patients and 10 healthy controls underwent (11)C-(R)-PK11195 PET and completed questionnaires about fatigue, fatigue sensation, cognitive impairments, pain, and depression. To measure the density of translocator protein, nondisplaceable binding potential (BP(ND)) values were determined using linear graphical analysis with the cerebellum as a reference region. RESULTS: The BP(ND) values of (11)C-(R)-PK11195 in the cingulate cortex, hippocampus, amygdala, thalamus, midbrain, and pons were 45%-199% higher in CFS/ME patients than in healthy controls. In CFS/ME patients, the BP(ND) values of (11)C-(R)-PK11195 in the amygdala, thalamus, and midbrain positively correlated with cognitive impairment score, the BP(ND) values in the cingulate cortex and thalamus positively correlated with pain score, and the BP(ND) value in the hippocampus positively correlated with depression score. CONCLUSION: Neuroinflammation is present in widespread brain areas in CFS/ME patients and was associated with the severity of neuropsychologic symptoms. Evaluation of neuroinflammation in CFS/ME patients may be essential for understanding the core pathophysiology and for developing objective diagnostic criteria and effective medical treatments.

  Jun. 2014, Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 55(6) (6), 945 - 50, English, International magazine

  Scientific journal


• Pd0-mediated rapid cross-coupling reactions, the rapid C-[11C]methylations, revolutionarily advancing the syntheses of short-lived PET molecular probes.

  Masaaki Suzuki, Hisashi Doi, Hiroko Koyama, Zhouen Zhang, Takamitsu Hosoya, Hirotaka Onoe, Yasuyoshi Watanabe

  Positron emission tomography is a noninvasive method for monitoring drug (or diagnostic) behavior and its localization on the target molecules in the living systems, including the human body, using a short-lived positron-emitting radionuclide. New methodologies for introducing representative short-lived radionuclides, (11)C and (18)F, into the carbon frameworks of biologically active organic compounds have been established by developing rapid C-[(11)C]methylations and C-[(18)F]fluoromethylations using rapid Pd(0)-mediated cross-coupling reactions between [(11)C]methyl iodide (sp(3)-hybridized carbon) and an excess amount of organotributylstannane or organoboronic acid ester having sp(2) (phenyl, heteroaromatic, or alkenyl), sp(alkynyl), or sp(3) (benzyl and cinnamyl)-hybridized carbons; and [(18)F]fluoromethyl halide (iodide or bromide) and an organoboronic acid ester, respectively. These rapid reactions provide a firm foundation for an efficient and general synthesis of short-lived (11)C- or (18)F-labeled PET molecular probes to promote in vivo molecular imaging studies.

  Jun. 2014, Chemical record (New York, N.Y.), 14(3) (3), 516 - 41, English, International magazine

  Scientific journal


• Neural effects of mental fatigue caused by continuous attention load: a magnetoencephalography study.

  Masaaki Tanaka, Akira Ishii, Yasuyoshi Watanabe

  Mental fatigue can be defined as a psychobiological state caused by prolonged periods of demanding cognitive activity and manifests as a reduced efficiency in cognitive performance. Mental fatigue is one of the most significant causes of accidents in modern society. Therefore, understanding the neural mechanisms of mental fatigue is important. However, the neural mechanisms of mental fatigue are not fully understood. In this study, we investigated the neural activity that results from mental fatigue caused by a continuous attention load. We used magnetoencephalography (MEG) to evaluate the neural activities during the attention task. Ten healthy male volunteers participated in this study. They performed a continuous attention task lasting 10 min. Subjective ratings of mental fatigue, mental stress, boredom, and sleepiness were performed just after the task trial. MEG data were analyzed using narrow-band adaptive spatial filtering methods. An increase in the beta-frequency band (13-25 Hz) power in the right inferior and middle frontal gyri (Brodmann׳s areas 44 and 9 respectively) was caused by the mental fatigue. The increase in the beta-frequency band power in the right middle frontal gyrus was negatively associated with the self-reported level of mental stress and was positively associated with those of boredom and sleepiness. These results demonstrate that performing a continuous mental fatigue-inducing task causes changes in the activation of the prefrontal cortex, and manifests as an increased beta-frequency power in this brain area as well as sleepiness. Our results contribute to greater understanding of the neural mechanisms of mental fatigue.

  May 2014, Brain research, 1561, 60 - 6, English, International magazine

  Scientific journal


• タウイメージング用放射性薬剤[11C]PBB3の大阪市立大学での臨床研究に向けた合成検討

  徳田 安則, 山岡 高章, 小畑 久子, 張 明栄, 島田 斉, 樋口 真人, 須原 哲也, 渡辺 恭良, 高橋 和弘

  日本分子イメージング学会, May 2014, JSMI Report, 7(2) (2), 127 - 127, Japanese


• Regulatory mechanism of performance in chronic cognitive fatigue.

  Masaaki Tanaka, Akira Ishii, Yasuyoshi Watanabe

  Chronic cognitive fatigue is characterized by a sensation of long-lasting fatigue that impairs cognitive functions. Facilitation and inhibition systems in the central nervous system play primary roles in determining the output to the peripheral system, that is, performance. Sensory input from the peripheral system to the central nervous system activates the inhibition system to limit performance, whereas motivational input activates the facilitation system to enhance performance. The dysfunction of the facilitation system and central sensitization and classical conditioning of the inhibition system play important roles in the pathophysiology of chronic cognitive fatigue. Because the dorsolateral prefrontal cortex receives input from both the facilitation and inhibition systems to determine performance, metabolic, functional, and structural impairments of the dorsolateral prefrontal cortex induced by repetitive and prolonged overwork, stress, and stress responses contribute to the impaired functioning and cognitive performance that occur in people with chronic cognitive fatigue. This hypothesis of the regulatory mechanism of performance provides a new perspective on the neural mechanisms underlying chronic cognitive fatigue.

  May 2014, Medical hypotheses, 82(5) (5), 567 - 71, English, International magazine

  Scientific journal


• PET imaging analysis with 64Cu in disulfiram treatment for aberrant copper biodistribution in Menkes disease mouse model.

  Shiho Nomura, Satoshi Nozaki, Takashi Hamazaki, Taisuke Takeda, Eiichi Ninomiya, Satoshi Kudo, Emi Hayashinaka, Yasuhiro Wada, Tomoko Hiroki, Chie Fujisawa, Hiroko Kodama, Haruo Shintaku, Yasuyoshi Watanabe

  UNLABELLED: Menkes disease (MD), an X-linked recessive disorder of copper metabolism caused by mutations in the copper-transporting ATP7A gene, results in growth failure and severe neurodegeneration in early childhood. Subcutaneous copper-histidine injection is the standard treatment for MD, but it has limited clinical efficacy. Furthermore, long-term copper injection causes excess copper accumulation in the kidneys, resulting in renal dysfunction. To attempt to resolve this issue, we used PET imaging with (64)Cu to investigate the effects of disulfiram on copper biodistribution in living mice serving as an animal model for MD (MD model mice). METHODS: Macular mice were used as MD model mice, and C3H/He mice were used as wild-type mice. Mice were pretreated with 2 types of chelators (disulfiram, a lipophilic chelator, and d-penicillamine, a hydrophilic chelator) 30 min before (64)CuCl2 injection. After (64)CuCl2 injection, emission scans covering the whole body were performed for 4 h. After the PET scans, the brain and kidneys were analyzed for radioactivity with γ counting and autoradiography. RESULTS: After copper injection alone, marked accumulation of radioactivity ((64)Cu) in the liver was demonstrated in wild-type mice, whereas in MD model mice, copper was preferentially accumulated in the kidneys (25.56 ± 3.01 percentage injected dose per gram [%ID/g]) and was detected to a lesser extent in the liver (13.83 ± 0.26 %ID/g) and brain (0.96 ± 0.08 %ID/g). Copper injection with disulfiram reduced excess copper accumulation in the kidneys (14.54 ± 2.68 %ID/g) and increased copper transport into the liver (29.42 ± 0.98 %ID/g) and brain (5.12 ± 0.95 %ID/g) of MD model mice. Copper injection with d-penicillamine enhanced urinary copper excretion and reduced copper accumulation in most organs in both mouse groups. Autoradiography demonstrated that disulfiram pretreatment induced copper transport into the brain parenchyma and reduced copper accumulation in the renal medulla. CONCLUSION: PET studies with (64)Cu revealed that disulfiram had significant effects on the copper biodistribution of MD. Disulfiram increased copper transport into the brain and reduced copper uptake in the kidneys of MD model mice. The application of (64)Cu PET for the treatment of MD and other copper-related disorders may be useful in clinical settings.

  May 2014, Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 55(5) (5), 845 - 51, English, International magazine

  Scientific journal


• 11C-cetrozole: an improved C-11C-methylated PET probe for aromatase imaging in the brain.

  Kayo Takahashi, Takamitsu Hosoya, Kayo Onoe, Hisashi Doi, Hiroko Nagata, Toshiyuki Hiramatsu, Xiao-Le Li, Yumiko Watanabe, Yasuhiro Wada, Tadayuki Takashima, Masaaki Suzuki, Hirotaka Onoe, Yasuyoshi Watanabe

  UNLABELLED: Aromatase (an enzyme that converts androgens to estrogens) in the brain is involved in neuroprotection, synaptic plasticity, and regulation of sexual and emotional behaviors. To investigate the physiologic and pathologic importance of aromatase in the brain, including in humans, we here report the development of a novel PET probe for aromatase, (11)C-cetrozole, which allows noninvasive quantification of aromatase expression. METHODS: (11)C-cetrozole was synthesized by the C-(11)C-methylation method developed by our group. In vitro autoradiography of frozen sections and a binding study with rat brain homogenates were conducted to demonstrate the specific binding and the dissociation constant. PET studies with anesthetized rhesus monkeys were performed to analyze the dynamics in the brain. RESULTS: In vitro and in vivo studies using (11)C-cetrozole showed its superiority in brain aromatase imaging in terms of specificity and selectivity, compared with previously developed (11)C-vorozole. PET studies showed that (11)C-cetrozole had a higher signal-to-noise ratio, providing a sharper image than (11)C-vorozole, because the radioactive metabolite of (11)C-vorozole was taken up into the brain. High specific binding of (11)C-cetrozole was observed in the amygdala and hypothalamus, and we also noted binding in the nucleus accumbens of rhesus monkeys for the first time. CONCLUSION: These results suggest that PET imaging with newly developed (11)C-cetrozole is suitable for quantifying the expression of brain aromatase in vivo, possibly providing critical information regarding the functional roles of aromatase in human neurologic and emotional disorders.

  May 2014, Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 55(5) (5), 852 - 7, English, International magazine

  Scientific journal


• 樹状型ポリエチレングリコール修飾によるボンベシンアナログ誘導体PETプローブの腫瘍内貯留性向上

  向井 英史, 松村 一史, 造田 真希, 高橋 麻衣子, 林中 恵美, 山下 富義, 橋田 充, 和田 康弘, 渡辺 恭良

  日本分子イメージング学会, May 2014, JSMI Report, 7(2) (2), 111 - 111, Japanese

  [Refereed]


• 64Cu標識前立腺癌標的ペプチドDUP-1の化学修飾がもたらす代謝安定性と腫瘍集積性の向上

  松村 一史, 向井 英史, 造田 真希, 高橋 麻衣子, 林中 恵美, 山下 富義, 橋田 充, 和田 康弘, 渡辺 恭良

  日本分子イメージング学会, May 2014, JSMI Report, 7(2) (2), 118 - 118, Japanese

  [Refereed]


• 11C標識TelbivudineによるB型肝炎モデルマウスのPETイメージング

  金山 洋介, 佐古 健生, 張 周恩, 蔵地 理代, Hume William Ewan, 林中 恵美, 和田 康弘, 崔 翼龍, 小嶋 聡一, 渡辺 恭良

  日本分子イメージング学会, May 2014, JSMI Report, 7(2) (2), 120 - 120, Japanese


• Positron Emission Tomography(PET)を用いた経鼻吸収評価系の構築と脳への直接移行性に関する研究

  新垣 友隆, 片山 由美子, 和田 康弘, 崔 翼龍, 古林 呂之, 坂根 稔康, 渡辺 恭良

  (公社)日本薬剤学会, May 2014, 日本薬剤学会年会講演要旨集, 29年会, 159 - 159, Japanese


• Quantitative evaluation of the improvement in the pharmacokinetics of a nucleic acid drug delivery system by dynamic PET imaging with F-18-incorporated oligodeoxynucleotides

  Hidefumi Mukai, Daiki Ozaki, Yilong Cui, Takeshi Kuboyama, Hiroko Yamato-Nagata, Kayo Onoe, Maiko Takahashi, Yasuhiro Wada, Takeshi Imanishi, Tetsuya Kodama, Satoshi Obika, Masaaki Suzuki, Hisashi Doi, Yasuyoshi Watanabe

  Apr. 2014, JOURNAL OF CONTROLLED RELEASE, 180, 92 - 99, English, International magazine

  [Refereed]

  Scientific journal


• 適度な血中循環の延長と多点認識を目指した化学修飾による癌PETイメージング用ペプチドプローブの改良

  松村 一史, 向井 英史, 造田 真希, 高橋 麻衣子, 林中 恵美, 川上 茂, 山下 富義, 橋田 充, 和田 康弘, 渡辺 恭良

  (公社)日本薬学会, Mar. 2014, 日本薬学会年会要旨集, 134年会(2) (2), 254 - 254, Japanese

  [Refereed]


• Neural regulatory mechanism of desire for food: revealed by magnetoencephalography.

  Takahiro Yoshikawa, Masaaki Tanaka, Akira Ishii, Shigeo Fujimoto, Yasuyoshi Watanabe

  Jan. 2014, Brain research, 1543, 120 - 7, English, International magazine

  Scientific journal


• Neural effect of mental fatigue on physical fatigue: a magnetoencephalography study.

  Masaaki Tanaka, Akira Ishii, Yasuyoshi Watanabe

  We sought to clarify the neural effect of mental fatigue on physical fatigue using magnetoencephalography (MEG) and classical conditioning techniques. Eleven right-handed volunteers participated in this study. On the first day, participants performed fatigue-inducing maximum handgrip trials for 10 min; metronome sounds were started 5 min after the beginning of the trials. We used metronome sounds as conditioned stimuli and maximum handgrip trials as unconditioned stimuli to cause physical fatigue. On the next day, MEG recordings during the imagery of maximum grips of the right hand guided by the metronome sounds were performed for 10 min just before (control session) and after (mental fatigue session) a 30-min fatigue-inducing mental task session. In the right anterior cingulate cortex (Brodmann's area 23), the alpha-band event-related synchronization of the mental fatigue session relative to the control session within the time window of 500–600 ms after the onset of handgrip cue sounds was identified. We demonstrated that mental fatigue suppresses activities in the right anterior cingulate cortex during physical fatigue.

  Jan. 2014, Brain research, 1542, 49 - 55, English, International magazine

  Scientific journal


• 6.PETによるC-11標識フルスルチアミン・チアミンの体内動態(第435回研究協議会研究発表要旨,ビタミンB研究委員会)

  渡辺 恭良, 土居 久志, 馬渡 彩, 金澤 奨勝, 野崎 聡, 中谷 友香, 野村 之博, 秋元 浩二, 二宮 伸二

  公益社団法人 日本ビタミン学会, 2014, ビタミン, 88(5) (5), 309 - 310, Japanese


• Brain interleukin-1β and the intrinsic receptor antagonist control peripheral Toll-like receptor 3-mediated suppression of spontaneous activity in rats.

  Masanori Yamato, Yasuhisa Tamura, Asami Eguchi, Satoshi Kume, Yukiharu Miyashige, Masayuki Nakano, Yasuyoshi Watanabe, Yosky Kataoka

  During acute viral infections such as influenza, humans often experience not only transient fever, but also prolonged fatigue or depressive feelings with a decrease in social activity for days or weeks. These feelings are thought to be due to neuroinflammation in the brain. Recent studies have suggested that chronic neuroinflammation is a precipitating event of various neurological disorders, but the mechanism determining the duration of neuroinflammation has not been elucidated. In this study, neuroinflammation was induced by intraperitoneal injection of polyriboinosinic:polyribocytidylic acid (poly I:C), a Toll-like receptor-3 agonist that mimics viral infection in male Sprague-Dawley rats, and then investigated how the neuroinflammation shift from acute to the chronic state. The rats showed transient fever and prolonged suppression of spontaneous activity for several days following poly I:C injection. NS-398, a cyclooxygenase-2 inhibitor, completely prevented fever, but did not improve spontaneous activity, indicating that suppression of spontaneous activity was not induced by the arachidonate cascade that generated the fever. The animals overexpressed interleukin (IL)-1β and IL-1 receptor antagonist (IL-1ra) in the brain including the cerebral cortex. Blocking the IL-1 receptor in the brain by intracerebroventricular (i.c.v.) infusion of recombinant IL-1ra completely blocked the poly I:C-induced suppression of spontaneous activity and attenuated amplification of brain interferon (IFN)-α expression, which has been reported to produce fatigue-like behavior by suppressing the serotonergic system. Furthermore, i.c.v. infusion of neutralizing antibody for IL-1ra prolonged recovery from suppression of spontaneous activity. Our findings indicated that IL-1β is the key trigger of neuroinflammation and that IL-1ra prevents the neuroinflammation entering the chronic state.

  2014, PloS one, 9(3) (3), e90950, English, International magazine

  Scientific journal


• The neural substrates of self-evaluation of mental fatigue: a magnetoencephalography study.

  Akira Ishii, Masaaki Tanaka, Yasuyoshi Watanabe

  There have been several studies of the neural mechanisms underlying sensation of fatigue. However, little is known about the neural mechanisms underlying self-evaluation of the level of fatigue. The aim of this study was to identify the neural substrates involved in self-evaluation of the level of mental fatigue. We used magnetoencephalography (MEG) with high temporal resolution on 14 healthy participants. During MEG recordings, participants were asked to evaluate their level of mental fatigue in time with execution cues (evaluation trials) or to do nothing in time with execution cues (control trials). The MEG data were analyzed with equivalent current dipole (ECD) and spatial filtering methods to localize the neural activity related to the evaluation of mental fatigue. The daily level of fatigue sensation was assessed using the Checklist Individual Strength questionnaire. In evaluation trials, ECDs were observed in the posterior cingulate cortex (PCC) in seven of 14 participants, with a mean latency of 366.0 ms. The proportion of the participants with ECDs in the PCC was higher in evaluation trials than in control trials (P<0.05, McNemar test). The extent of the decreased delta band power in the PCC (Brodmann's area 31) 600-700 ms after the onset of the execution cue and that in the dorsolateral prefrontal cortex (DLPFC; Brodmann's area 9) 800-900 ms after the onset of the execution cue were greater in the evaluation trials than in the control trials. The decrease in delta band power in the DLPFC was positively related to that in the PCC and to the daily level of fatigue sensation. These data suggest that the PCC and DLPFC are involved in the self-evaluation of mental fatigue.

  2014, PloS one, 9(4) (4), e95763, English, International magazine

  Scientific journal


• Neural mechanisms of mental fatigue.

  Akira Ishii, Masaaki Tanaka, Yasuyoshi Watanabe

  Fatigue is defined as a decline in the ability and efficiency of mental and/or physical activities that is caused by excessive mental and/or physical activities. Fatigue can be classified as physical or mental. Mental fatigue manifests as potentially impaired cognitive function and is one of the most significant causes of accidents in modern society. Recently, it has been shown that the neural mechanisms of mental fatigue related to cognitive task performance are more complex than previously thought and that mental fatigue is not caused only by impaired activity in task-related brain regions. There is accumulating evidence supporting the existence of mental facilitation and inhibition systems. These systems are involved in the neural mechanisms of mental fatigue, modulating the activity of task-related brain regions to regulate cognitive task performance. In this review, we propose a new conceptual model: the dual regulation system of mental fatigue. This model contributes to our understanding of the neural mechanisms of mental fatigue and the regulatory mechanisms of cognitive task performance in the presence of mental fatigue.

  2014, Reviews in the neurosciences, 25(4) (4), 469 - 79, English, International magazine

  Scientific journal


• Association of fatigue with emotional-eating behavior and the response to mental stress in food intake in a young adult population.

  Takahiro Yoshikawa, Masaaki Tanaka, Akira Ishii, Yasuyoshi Watanabe

  2014, Behavioral medicine (Washington, D.C.), 40(4) (4), 149 - 53, English, International magazine

  Scientific journal


• The neural mechanisms underlying the decision to rest in the presence of fatigue: a magnetoencephalography study.

  Akira Ishii, Masaaki Tanaka, Yasuyoshi Watanabe

  Adequate rest is essential to avoid fatigue and disruption of homeostasis. However, the neural mechanisms underlying the decision to rest are not well understood. In the present study, we aimed to clarify the neural mechanisms of this decision-making process using magnetoencephalography. Fifteen healthy volunteers participated in decision and control experiments performed in a cross-over fashion. In the decision experiment, participants performed 1,200 reverse Stroop test trials and were intermittently asked to decide whether they wanted to take a rest or continue. In the control experiments, participants performed 1,200 reverse Stroop test trials and were instructed to press a response button intermittently without making any decision. Changes in oscillatory brain activity were assessed using a narrow-band adaptive spatial filtering method. The levels of decrease in theta (4-8 Hz) band power in left Brodmann's area (BA) 31, alpha (8-13 Hz) band power in left BA 10 and BA 9, and beta (13-25 Hz) band power in right BA 46 and left BA 10 were greater in trials when the participant opted to rest (rest trials) than those in control trials. The decrease in theta band power in BA 31 in the rest trials was positively correlated with the subjective level of fatigue after the decision experiment. These results demonstrated that the dorsolateral prefrontal cortex, frontal pole, and posterior cingulate cortex play a role in the decision to rest in the presence of fatigue. These findings may help clarify the neural mechanisms underlying fatigue and fatigue-related problems.

  2014, PloS one, 9(10) (10), e109740, English, International magazine

  Scientific journal


• The synthesis and biodistribution of [(11)C]metformin as a PET probe to study hepatobiliary transport mediated by the multi-drug and toxin extrusion transporter 1 (MATE1) in vivo.

  W Ewan Hume, Tomotaka Shingaki, Tadayuki Takashima, Yoshinobu Hashizume, Takashi Okauchi, Yumiko Katayama, Emi Hayashinaka, Yasuhiro Wada, Hiroyuki Kusuhara, Yuichi Sugiyama, Yasuyoshi Watanabe

  In order to develop a new positron emission tomography (PET) probe to study hepatobiliary transport mediated by the multi-drug and toxin extrusion transporter 1 (MATE1), (11)C-labelled metformin was synthesized and then evaluated as a PET probe. [(11)C]Metformin ([(11)C]4) was synthesized in three steps, from [(11)C]methyl iodide. Evaluation by small animal PET of [(11)C]4 showed that there was increased concentrations of [(11)C]4 in the livers of mice pre-treated with pyrimethamine, a potential inhibitor of MATEs, inhibiting the hepatobiliary excretion of metformin. Radiometabolite analysis showed that [(11)C]4 was not degraded in vivo during the PET scan. Biodistribution studies were undertaken and the organ distributions were extrapolated into a standard human model. In conclusion, [(11)C]4 may be useful as a PET probe to non-invasively study the in vivo function of hepatobiliary transport and drug-drug interactions, mediated by MATE1 in future clinical investigations.

  Dec. 2013, Bioorganic & medicinal chemistry, 21(24) (24), 7584 - 90, English, International magazine

  Scientific journal


• Positron emission tomography study on pancreatic somatostatin receptors in normal and diabetic rats with 68Ga-DOTA-octreotide: a potential PET tracer for beta cell mass measurement.

  Takeo Sako, Koki Hasegawa, Mie Nishimura, Yousuke Kanayama, Yasuhiro Wada, Emi Hayashinaka, Yilong Cui, Yosky Kataoka, Michio Senda, Yasuyoshi Watanabe

  Dec. 2013, Biochemical and biophysical research communications, 442(1-2) (1-2), 79 - 84, English, International magazine

  [Refereed]

  Scientific journal


• Neural mechanism of central inhibition during physical fatigue: a magnetoencephalography study.

  Masaaki Tanaka, Akira Ishii, Yasuyoshi Watanabe

  Central inhibition plays an important role in physical performance during physical fatigue. We tried to clarify the neural mechanism of central inhibition during physical fatigue using the magnetoencephalography (MEG) and a classical conditioning technique. Twelve right-handed volunteers participated in this study. Participants underwent MEG recording during the imagery of maximum grips of the right hand guided by metronome sounds for 10 min. Thereafter, fatigue-inducing maximum handgrip trials were performed for 10 min; the metronome sounds were started 5 min after the beginning of the handgrip trials. We used metronome sounds as conditioned stimuli and maximum handgrip trials as unconditioned stimuli to cause central inhibition. The next day, MEG recording during the imagery of maximum grips of the right hand guided by metronome sounds were measured for 10 min. Levels of the fatigue sensation in the right hand and sympathetic nerve activity on the second day were significantly higher than those on the first day. In the right dorsolateral prefrontal cortex (Brodmann's area 46), the alpha-band event-related desynchronization (ERD) of the second MEG session relative to the first session with the time window of 200 to 300 ms after the onset of handgrip cue sounds was identified. The ERD level in this brain region was positively associated with the change in subjective level of right hand fatigue after the conditioning session and was negatively associated with that of the sympathetic nerve activity. We demonstrated that the right dorsolateral prefrontal cortex is involved in the neural substrates of central inhibition during physical fatigue.

  Nov. 2013, Brain research, 1537, 117 - 24, English, International magazine

  Scientific journal


• Neural mechanisms of phonemic restoration for speech comprehension revealed by magnetoencephalography.

  Kishiko Sunami, Akira Ishii, Sakurako Takano, Hidefumi Yamamoto, Tetsushi Sakashita, Masaaki Tanaka, Yasuyoshi Watanabe, Hideo Yamane

  In daily communication, we can usually still hear the spoken words as if they had not been masked and can comprehend the speech when spoken words are masked by background noise. This phenomenon is known as phonemic restoration. Since little is known about the neural mechanisms underlying phonemic restoration for speech comprehension, we aimed to identify the neural mechanisms using magnetoencephalography (MEG). Twelve healthy male volunteers with normal hearing participated in the study. Participants were requested to carefully listen to and understand recorded spoken Japanese stories, which were either played forward (forward condition) or in reverse (reverse condition), with their eyes closed. Several syllables of spoken words were replaced by 300-ms white-noise stimuli with an inter-stimulus interval of 1.6-20.3s. We compared MEG responses to white-noise stimuli during the forward condition with those during the reverse condition using time-frequency analyses. Increased 3-5 Hz band power in the forward condition compared with the reverse condition was continuously observed in the left inferior frontal gyrus [Brodmann's areas (BAs) 45, 46, and 47] and decreased 18-22 Hz band powers caused by white-noise stimuli were seen in the left transverse temporal gyrus (BA 42) and superior temporal gyrus (BA 22). These results suggest that the left inferior frontal gyrus and left transverse and superior temporal gyri are involved in phonemic restoration for speech comprehension. Our findings may help clarify the neural mechanisms of phonemic restoration as well as develop innovative treatment methods for individuals suffering from impaired speech comprehension, particularly in noisy environments.

  Nov. 2013, Brain research, 1537, 164 - 73, English, International magazine

  Scientific journal


• 64Cu-DOTA-trastuzumab PET imaging in patients with HER2-positive breast cancer.

  Kenji Tamura, Hiroaki Kurihara, Kan Yonemori, Hitoshi Tsuda, Junko Suzuki, Yuzuru Kono, Natsuki Honda, Makoto Kodaira, Harukaze Yamamoto, Mayu Yunokawa, Chikako Shimizu, Koki Hasegawa, Yousuke Kanayama, Satoshi Nozaki, Takayuki Kinoshita, Yasuhiro Wada, Shusaku Tazawa, Kazuhiro Takahashi, Yasuyoshi Watanabe, Yasuhiro Fujiwara

  Nov. 2013, Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 54(11) (11), 1869 - 75, English, International magazine

  Scientific journal


• Evaluation of Oatp and Mrp2 activities in hepatobiliary excretion using newly developed positron emission tomography tracer [11C]dehydropravastatin in rats.

  Tomotaka Shingaki, Tadayuki Takashima, Ryosuke Ijuin, Xuan Zhang, Tomohiro Onoue, Yumiko Katayama, Takashi Okauchi, Emi Hayashinaka, Yilong Cui, Yasuhiro Wada, Masaaki Suzuki, Kazuya Maeda, Hiroyuki Kusuhara, Yuichi Sugiyama, Yasuyoshi Watanabe

  We developed a pravastatin derivative, sodium (3R,5R)-3,5-dihydroxy-7-((1S,2S,6S,8S)-6-hydroxy-2-methyl-8-((1-[(11)C]-(E)-2-methyl-but-2-enoyl)oxy)-1,2,6,7,8,8a-hexahydronaphthalen-1-yl)heptanoate ([(11)C]DPV), as a positron emission tomography (PET) probe for noninvasive measurement of hepatobiliary transport, and conducted pharmacokinetic analysis in rats as a feasibility study for future clinical study. Transport activities of DPV in freshly isolated rat hepatocytes and rodent multidrug resistance-associated protein 2 (rMrp2; human, MRP2)-expressing membrane vesicles were similar to those of pravastatin. Rifampicin diminished the uptake of DPV and pravastatin by the hepatocytes, with similar inhibition potency. [(11)C]DPV underwent biotransformation to produce at least two metabolites in rat, but metabolism of [(11)C]DPV occurred negligibly in human hepatocytes during a 90-minute incubation. After intravenous injection, [(11)C]DPV was mainly distributed to the liver and kidneys, where the tissue uptake clearances (CLuptake,liver and CLuptake,kidney) were blood-flow-limited (73.6 ± 4.8 and 24.6 ± 0.6 ml/min per kilogram, respectively). Systemic elimination of [(11)C]DPV was delayed in rifampicin-treated rat and an Mrp2-deficient mutant rat, Eisai hyperbilirubinemic mutant rat (EHBR). Rifampicin treatment decreased both CLuptake,liver and CLuptake,kidney of [(11)C]DPV by 30% (P < 0.05), whereas these parameters were unchanged in EHBR. Meanwhile, the canalicular efflux clearance (CLint,bile) of [(11)C]DPV, which was 12.2 ± 1.5 ml/min per kilogram in the control rat, decreased by 60% and 89% in rifampicin-treated rat and EHBR (P < 0.05), respectively. These results indicate that [(11)C]DPV is taken up into the liver by organic anion-transporting polypeptides (rodent, Oatps; human, OATP) and excreted into bile by Mrp2 in rat, and that rifampicin may inhibit Mrp2 as well as Oatps, and consequently increase systemic exposure of [(11)C]DPV. PET using [(11)C]DPV is feasible for studies prior to the future clinical investigation of OATP and MRP2 functionality, especially for personalized medicine.

  Oct. 2013, The Journal of pharmacology and experimental therapeutics, 347(1) (1), 193 - 202, English, International magazine

  [Refereed]

  Scientific journal


• Neural effects of prolonged mental fatigue: a magnetoencephalography study.

  Akira Ishii, Masaaki Tanaka, Yoshihito Shigihara, Etsuko Kanai, Masami Funakura, Yasuyoshi Watanabe

  Mental fatigue, manifest as a reduced efficiency for mental work load, is prevalent in modern society. It is important to understand the neural mechanisms of mental fatigue and to develop appropriate methods for evaluating mental fatigue. In this study we quantified the effect of a long-duration mental fatigue-inducing task on neural activity. We used magnetoencephalography (MEG) to examine the time course change of neural activity over the long duration of the task trials. Nine healthy male volunteers participated in this study. They performed two mental fatigue-inducing tasks on separate days. The order of task presentation was randomized in a single-blinded, crossover fashion. Each task consisted of 25-min mental fatigue-inducing 0- or 2-back task session for three times. Subjective rating of mental fatigue sensation and electrocardiogram, and resting state MEG measurements were performed just before and after each task session. MEG data were analyzed using narrow-band adaptive spatial filtering methods. Alpha band (8-13 Hz) power in the visual cortex decreased after performing the mental fatigue-inducing tasks, and the decrease of alpha power was greater when they performed 2-back task trials. The decrease in alpha power was positively associated with the self-reported level of mental fatigue sensation and sympathetic nerve activity level. These results demonstrate that performing the prolonged mental fatigue-inducing task causes overactivation of the visual cortex, manifest as decreased alpha power in this brain region. Our results increase understanding of the neural mechanisms of mental fatigue and can be used to develop new quantitative methods to assess mental fatigue.

  Sep. 2013, Brain research, 1529, 105 - 12, English, International magazine

  Scientific journal


• Investigation of the effect of active efflux at the blood-brain barrier on the distribution of nonsteroidal aromatase inhibitors in the central nervous system.

  Mari Miyajima, Hiroyuki Kusuhara, Kayo Takahashi, Tadayuki Takashima, Takamitsu Hosoya, Yasuyoshi Watanabe, Yuichi Sugiyama

  The brain distribution of nonsteroidal aromatase inhibitors was investigated in mice to understand their interactions with brain aromatase. The brain-to-plasma ratio (Kp,brain , mL/g brain) of anastrozole was 0.0299 ± 0.0068, which was lower than that of letrozole (0.383 ± 0.048) and vorozole (0.185 ± 0.031) despite their similar physicochemical properties. The brain-to-plasma unbound concentration ratio of anastrozole, measured using microdialysis, was 0.118 ± 0.037 mL/g brain. In situ mouse brain perfusion also demonstrated that the uptake clearance [mL/(min·g brain)] of anastrozole by the brain (0.108 ± 0.018) was lower than that for letrozole and vorozole (0.422 ± 0.068 and 0.910 ± 0.152, respectively). Anastrozole and vorozole were transported by P-glycoprotein (P-gp) in vitro, whereas none of the compounds were transported by breast cancer resistance protein (BCRP). The Kp,brain of anastrozole and vorozole were increased by 12- and 3.3-fold, respectively, in Mdr1a/b/Bcrp(-/-) mice. IC50 (nM) of anastrozole and letrozole against human aromatase was 12.9 ± 0.7 and 3.59 ± 0.75, respectively. Taken together, these results suggest that active efflux mediated by P-gp at the blood-brain barrier limits the effect of anastrozole in the central nervous system, whereas vorozole and letrozole easily traverse the barrier.

  Sep. 2013, Journal of pharmaceutical sciences, 102(9) (9), 3309 - 19, English, International magazine

  Scientific journal


• 64Cu標識ソマトスタチンアナログを用いた2型糖尿病モデルラットの膵内分泌細胞PETイメージング

  佐古 健生, 岡内 隆, 向井 英史, 松村 一史, 和田 康弘, 林中 恵美, 崔 翼龍, 千田 道雄, 渡辺 恭良

  (一社)日本核医学会, Sep. 2013, 核医学, 50(3) (3), S236 - S236, Japanese


• Autonomic function is associated with health-related quality of life in patients with end-stage renal disease: a case-control study.

  Fujii H, Koyama H, Fukuda S, Tokai H, Tajima S, Koizumi J, Yamaguti K, Kuratsune H, Watanabe Y, Hirayama Y, Shoji T, Inaba M, Nishizawa Y

  OBJECTIVE: In the present study, we assessed the associations among fatigue, quality of life (QOL), clinical parameters, and body mass index (BMI) with autonomic function in end-stage renal disease (ESRD) patients undergoing hemodialysis as well as fatigue-free healthy subjects. DESIGN AND METHODS: This was a case-control study. This study compared autonomic function in ESRD patients (n = 192) to that of healthy subjects (n = 282) and evaluated its association with fatigue, QOL, and clinical parameters such as glucose, albumin, cholesterol, and BMI. Fatigue was evaluated by a recently established fatigue questionnaire and performance status, and QOL was evaluated with the kidney disease QOL questionnaire. With regards to autonomic function, spontaneous beat-to-beat variations were measured, according to time- (standard deviation of all normal a-wave intervals [CVa-a%]) and frequency domains (low frequency [LF] power, high frequency [HF] power, and LF/HF ratio) with acceleration plethysmography. RESULTS: CVa-a%, LF power, HF power, and LF/HF ratio were significantly lower in ESRD patients than healthy subjects. There were significant inverse correlations between these factors and age in healthy subjects, but not in ESRD patients. Although the fatigue score was not associated with any autonomic parameters, ESRD patients with impaired performance status exhibited a significantly lower LF/HF ratio. Moreover, in ESRD patients, the LF/HF ratio was significantly and positively associated with several components of QOL, including physical functioning and role emotional, independent of other clinical parameters and BMI. CONCLUSIONS: Impaired autonomic function is significantly associated with fatigue and impaired QOL in dialysis patients.

  Sep. 2013, Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation, 23(5) (5), 340 - 347, English, International magazine

  [Refereed]

  Scientific journal


• Immediate neural responses of appetitive motives and its relationship with hedonic appetite and body weight as revealed by magnetoencephalography.

  Takahiro Yoshikawa, Masaaki Tanaka, Akira Ishii, Yasuyoshi Watanabe

  Aug. 2013, Medical science monitor : international medical journal of experimental and clinical research, 19, 631 - 40, English, International magazine

  Scientific journal


• The synthesis of Cu-64-chelated porphyrin photosensitizers and their tumor-targeting peptide conjugates for the evaluation of target cell uptake and PET image-based pharmacokinetics of targeted photodynamic therapy agents

  Hidefumi Mukai, Yasuhiro Wada, Yasuyoshi Watanabe

  Aug. 2013, ANNALS OF NUCLEAR MEDICINE, 27(7) (7), 625 - 639, English, Domestic magazine

  [Refereed]

  Scientific journal


• Effects of chicken essence on recovery from mental fatigue in healthy males.

  Emi Yamano, Masaaki Tanaka, Akira Ishii, Nobuo Tsuruoka, Keiichi Abe, Yasuyoshi Watanabe

  BACKGROUND: Fatigue is a common symptom in modern society. There has been a recent resurgence of interest in traditional remedies for fatigue. Chicken essence, which is rich in anserine and carnosine, has been widely taken in Asian countries as a traditional remedy with various aims, including attenuation of physical and mental fatigue. However, the evidence for its efficacy specifically for mental fatigue remains unclear. We examined the effect of essence of chicken on mental fatigue in humans, using our established fatigue-inducing task and evaluation methods. MATERIAL AND METHODS: In this placebo-controlled crossover study, 20 healthy male volunteers were randomized to receive daily oral administration of essence of chicken or placebo drink provided by Cerebos Pacific Ltd. via Suntory holdings Ltd. for 4 weeks. The participants performed 2-back test trials as a fatigue-inducing mental task and then had a rest session. Just before and after each session, they completed cognitive task trials focusing on selective attention to evaluate the level of mental fatigue. RESULTS: After essence of chicken intake for 1 and 4 weeks, the reaction times on the cognitive task trials after the rest session were significantly shorter than those at baseline, and significant changes were not observed with placebo intake. The reaction times before and after the fatigue-inducing session were not altered by either essence of chicken or placebo intake. CONCLUSIONS: We showed that daily intake of essence of chicken could be effective for the recovery from mental fatigue and is a promising candidate for use as an anti-fatigue food.

  Jul. 2013, Medical science monitor : international medical journal of experimental and clinical research, 19, 540 - 7, English, International magazine

  Scientific journal


• Synthesis of an 11C-labeled antiprion gn8 derivative and evaluation of its brain uptake by positron emission tomography

  Tsutomu Kimura, Takeo Sako, Siqin, Junji Hosokawa-Muto, Yi Long Cui, Yasuhiro Wada, Yosky Kataoka, Hisashi Doi, Suehiro Sakaguchi, Masaaki Suzuki, Yasuyoshi Watanabe, Kazuo Kuwata

  Jul. 2013, ChemMedChem, 8(7) (7), 1035 - 1039, English, International magazine

  [Refereed]

  Scientific journal


• Fatigue sensation induced by the sounds associated with mental fatigue and its related neural activities: revealed by magnetoencephalography.

  Akira Ishii, Masaaki Tanaka, Masayoshi Iwamae, Chongsoo Kim, Emi Yamano, Yasuyoshi Watanabe

  BACKGROUND: It has been proposed that an inappropriately conditioned fatigue sensation could be one cause of chronic fatigue. Although classical conditioning of the fatigue sensation has been reported in rats, there have been no reports in humans. Our aim was to examine whether classical conditioning of the mental fatigue sensation can take place in humans and to clarify the neural mechanisms of fatigue sensation using magnetoencephalography (MEG). METHODS: Ten and 9 healthy volunteers participated in a conditioning and a control experiment, respectively. In the conditioning experiment, we used metronome sounds as conditioned stimuli and two-back task trials as unconditioned stimuli to cause fatigue sensation. Participants underwent MEG measurement while listening to the metronome sounds for 6 min. Thereafter, fatigue-inducing mental task trials (two-back task trials), which are demanding working-memory task trials, were performed for 60 min; metronome sounds were started 30 min after the start of the task trials (conditioning session). The next day, neural activities while listening to the metronome for 6 min were measured. Levels of fatigue sensation were also assessed using a visual analogue scale. In the control experiment, participants listened to the metronome on the first and second days, but they did not perform conditioning session. MEG was not recorded in the control experiment. RESULTS: The level of fatigue sensation caused by listening to the metronome on the second day was significantly higher relative to that on the first day only when participants performed the conditioning session on the first day. Equivalent current dipoles (ECDs) in the insular cortex, with mean latencies of approximately 190 ms, were observed in six of eight participants after the conditioning session, although ECDs were not identified in any participant before the conditioning session. CONCLUSIONS: We demonstrated that the metronome sounds can cause mental fatigue sensation as a result of repeated pairings of the sounds with mental fatigue and that the insular cortex is involved in the neural substrates of this phenomenon.

  Jun. 2013, Behavioral and brain functions : BBF, 9, 24 - 24, English, International magazine

  Scientific journal


• 治療と介入 慢性疲労症候群における還元型コエンザイムQ10の効果 二重盲検群間比較試験

  福田 早苗, 中富 康仁, 山口 浩二, 野島 順三, 近藤 一博, 梶本 修身, 倉恒 弘彦, 渡辺 恭良

  日本疲労学会, Jun. 2013, 日本疲労学会誌, 9(1) (1), 76 - 76, Japanese


• Dynamic Analysis of Fluid Distribution in the Gastrointestinal Tract in Rats: Positron Emission Tomography Imaging after Oral Administration of Nonabsorbable Marker, [F-18]Deoxyfluoropoly(ethylene glycol)

  Tadayuki Takashima, Tomotaka Shingaki, Yumiko Katayama, Emi Hayashinaka, Yasuhiro Wada, Makoto Kataoka, Daiki Ozaki, Hisashi Doi, Masaaki Suzuki, Sho Ishida, Kentaro Hatanaka, Yuichi Sugiyama, Shuji Akai, Naoto Oku, Shinji Yamashita, Yasuyoshi Watanabe

  Jun. 2013, MOLECULAR PHARMACEUTICS, 10(6) (6), 2261 - 2269, English, International magazine

  [Refereed]

  Scientific journal


• Chronic degeneration of dorsal raphe serotonergic neurons modulates cortical spreading depression: A possible pathophysiology of migraine

  Yilong Cui, Qing-Hua Li, Hisao Yamada, Yasuyoshi Watanabe, Yosky Kataoka

  Jun. 2013, JOURNAL OF NEUROSCIENCE RESEARCH, 91(6) (6), 737 - 744, English, International magazine

  [Refereed]

  Scientific journal


• 経鼻投与を用いた薬物送達法の評価に対するPositron Emission Tomography(PET)の活用

  新垣 友隆, 片山 由美子, 岡内 隆, 林中 恵美, 和田 康弘, 古林 呂之, 坂根 稔康, 崔 翼龍, 渡辺 恭良

  日本DDS学会, Jun. 2013, 日本DDS学会学術集会プログラム予稿集, 29回, 184 - 184, Japanese


• Divided attention of adolescents related to lifestyles and academic and family conditions.

  Kei Mizuno, Masaaki Tanaka, Sanae Fukuda, Kyoko Imai-Matsumura, Yasuyoshi Watanabe

  BACKGROUND: Development of the ability to divide attention is of crucial importance in the transitional period from elementary to junior high school. The relationship between divided attention and the prevalence of fatigue or low academic motivation is observed in junior high school students. In order to clarify the factors underlying decreased ability to divide attention, we examined the relationships between divided attention, as assessed by the kana pick-out test, lifestyle factors, and academic and family conditions in junior high school students. METHODS: The study group consisted of 158 healthy 1st-, 2nd-, and 3rd-grade level junior high school students. Each participant performed the kana pick-out test and questionnaires dealing with lifestyle factors (nocturnal sleeping hours on school days, breakfast, exercise, watching television, and spending time with family members), and academic and family conditions (good friendships at school and praise from family members when participants showed good academic performance). RESULTS: On multiple regression analyses adjusted for grade and gender, scores on the kana pick-out test were positively associated with spending time with family members. In addition, the comprehension score of the kana pick-out test was positively associated with having breakfast every day and praise by family members. The score was negatively associated with watching television. CONCLUSION: The present findings suggest that the ability to divide attention is independently associated with good lifestyles and academic and family conditions in junior high school students.

  May 2013, Brain & development, 35(5) (5), 435 - 40, English, International magazine

  Scientific journal


• A conformationally fixed analog of the peptide mimic Grb2-SH2 domain: synthesis and evaluation against the A431 cancer cell.

  Takayuki Iwata, Katsunori Tanaka, Tsuyoshi Tahara, Satoshi Nozaki, Hirotaka Onoe, Yasuyoshi Watanabe, Koichi Fukase

  A small peptide mimic of the Grb2-SH2 domain, which was previously prepared through the template-assisted click approach and exhibited selective A431 tumor growth inhibition both in vitro and in vivo, was further elaborated on to enhance the interaction with target phosphorylated proteins. A conformationally fixed analog was efficiently synthesized by solid-supported ring-closing metathesis and Cu(i)/His-mediated self-activating Huisgen [3+2] cycloadditon as the key steps, and exhibited a 10-fold enhanced affinity to a phosphorylated peptide, a truncated peptide analog of the Grb2-SH2-interacting phosphoproteins. A stronger interaction with the target phosphorylated proteins gave this cyclic analog cytotoxic activity in A431 cells.

  May 2013, Molecular bioSystems, 9(5) (5), 1019 - 25, English, International magazine

  Scientific journal


• 片頭痛モデル動物を用いたオピオイド受容体のPETイメージング

  崔 翼龍, 長田 浩子, 佐古 健生, 林中 恵美, 和田 康弘, 土居 久志, 渡辺 恭良

  日本分子イメージング学会, May 2013, JSMI Report, 6(2) (2), 82 - 82, Japanese


• Positron Emission Tomography(PET)による経鼻吸収評価系の確立

  新垣 友隆, 片山 由美子, 岡内 隆, 林中 恵美, 和田 康弘, 古林 呂之, 坂根 稔康, 崔 翼龍, 渡辺 恭良

  日本分子イメージング学会, May 2013, JSMI Report, 6(2) (2), 94 - 94, Japanese


• Relationship between appetitive motives and non-exercise lifestyle in a young adult population.

  Takahiro Yoshikawa, Keisuke Orita, Yasuyoshi Watanabe, Masaaki Tanaka

  Apr. 2013, Medical science monitor : international medical journal of experimental and clinical research, 19, 289 - 94, English, International magazine

  Scientific journal


• c-Fos activity mapping reveals differential effects of noradrenaline and serotonin depletion on the regulation of ocular dominance plasticity in rats.

  K Nakadate, K Imamura, Y Watanabe

  The roles of the central noradrenergic and serotonergic system in the activity-dependent regulation of ocular dominance plasticity have been a contentious issue. Using c-Fos activity mapping, we have developed a new, straightforward method to measure the strength of ocular dominance plasticity: the number of c-Fos-immunopositive cells in layer IV of rat visual cortex (Oc1B), ipsilateral to the stimulated eye, is a sensitive and reliable measure of the effects of monocular deprivation. Applying this new method, here we studied the unique modification of the degree of c-Fos expression induced in the visual cortex, in that endogenous noradrenaline (NA) and serotonin (5HT) in the cortex were significantly reduced, respectively by specific pharmacological agents. Intraperitoneal injections of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) and p-chlorophenylalanine (pCPA) selectively impair NA- and 5HT-containing nerve terminals and fibers, respectively. In the visual cortex with strongly reduced NA, the number of c-Fos-immunopositive cells was found remaining significantly decreased in response to stimulation of the deprived eye, while by open eye stimulation the expected increase in c-Fos-immunoreactivity was strongly suppressed, showing values not different from those obtained by monocular stimulation in the normal rats. In contrast, in the visual cortex with strongly reduced 5HT no expected decrease was found in response to stimulation of the deprived eye, while, as is usually the case for the normal animals, a significant increase was still induced in response to open eye stimulation. These findings suggest that the noradrenergic and serotonergic system regulate ocular dominance (OD) plasticity differently: in the NA-depleted cortex the expected increase in c-Fos expression by open eye stimulation was not seen due to strong suppression, whereas in 5HT-depletion, the expected decrease in c-Fos expression was not materialized due to strong suppression. The present findings with c-Fos activity mapping method indicated a novel possibility of the differential regulation of OD plasticity by two types of common monoaminergic systems.

  Apr. 2013, Neuroscience, 235, 1 - 9, English, International magazine

  [Refereed]

  Scientific journal


• 骨粗鬆症治療薬Teriparatideの副作用メカニズム解明のためのPositron Emission Tomography(PET)有用性評価

  新垣 友隆, 片山 由美子, 岡内 隆, 林中 恵美, 和田 康弘, 加藤 直人, 黒田 龍彦, 崔 翼龍, 渡辺 恭良

  (公社)日本薬剤学会, Apr. 2013, 日本薬剤学会年会講演要旨集, 28年会, 282 - 282, Japanese


• Detection of early stage atherosclerotic plaques using PET and CT fusion imaging targeting P-selectin in low density lipoprotein receptor-deficient mice.

  Ikuko Nakamura, Koki Hasegawa, Yasuhiro Wada, Tetsuaki Hirase, Koichi Node, Yasuyoshi Watanabe

  BACKGROUND: Sensitive detection and qualitative analysis of atherosclerotic plaques are in high demand in cardiovascular clinical settings. The leukocyte-endothelial interaction mediated by an adhesion molecule P-selectin participates in arterial wall inflammation and atherosclerosis. METHODS AND RESULTS: A (64)Cu-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid conjugated anti-P-selectin monoclonal antibody ((64)Cu-DOTA-anti-P-selectin mAb) probe was prepared by conjugating an anti-P-selectin monoclonal antibody with DOTA followed by (64)Cu labeling. Thirty-six hours prior to PET and CT fusion imaging, 3MBq of (64)Cu-DOTA-anti-P-selectin mAb was intravenously injected into low density lipoprotein receptor-deficient Ldlr-/- mice. After a 180min PET scan, autoradiography and biodistribution of (64)Cu-DOTA-anti-P-selectin monoclonal antibody was examined using excised aortas. In Ldlr-/- mice fed with a high cholesterol diet for promotion of atherosclerotic plaque development, PET and CT fusion imaging revealed selective and prominent accumulation of the probe in the aortic root. Autoradiography of aortas that demonstrated probe uptake into atherosclerotic plaques was confirmed by Oil red O staining for lipid droplets. In Ldlr-/- mice fed with a chow diet to develop mild atherosclerotic plaques, probe accumulation was barely detectable in the aortic root on PET and CT fusion imaging. Probe biodistribution in aortas was 6.6-fold higher in Ldlr-/- mice fed with a high cholesterol diet than in those fed with a normal chow diet. (64)Cu-DOTA-anti-P-selectin mAb accumulated selectively in aortic atherosclerotic plaques and was detectable by PET and CT fusion imaging in Ldlr-/- mice. CONCLUSIONS: P-selectin is a candidate target molecule for early-phase detection by PET and CT fusion imaging of atherosclerotic plaques.

  Mar. 2013, Biochemical and biophysical research communications, 433(1) (1), 47 - 51, English, International magazine

  Scientific journal


• Association of monoamine-synthesizing genes with the depression tendency and personality in chronic fatigue syndrome patients.

  Sanae Fukuda, Mieko Horiguchi, Kouzi Yamaguti, Yasuhito Nakatomi, Hirohiko Kuratsune, Hiroshi Ichinose, Yasuyoshi Watanabe

  AIMS: Tyrosine hydroxylase (TH) and GTP cyclohydrolase I (GCH) are the rate-limiting enzymes for the biosynthesis of catecholamines and tetrahydrobiopterin (BH4), respectively. Since catecholamines and BH4 are thought to be involved in the pathophysiology of CFS, we explored the genetic factors that influence CFS development and examined the possible association between the SNPs of the TH and GCH genes and the various characteristics of CFS patients. MAIN METHODS: After drawing venous blood from CFS patients and controls, genomic DNA was then extracted from whole blood in accordance with standard procedures. Digestion patterns of the PCR products were used for genotyping the SNPs of GCH (rs841; C+243T) and TH (rs10770141; C-824T). We also performed questionnaires consisting of fatigue-scale and temperament and character inventory scale (TCI) to CFS patients. KEY FINDINGS: Our results demonstrated that the allele differences for the GCH and TH SNPs were not associated with CFS patients. We did find that the GCH gene with the C+243T polymorphism affected harm avoidance, while the TH gene with the C-824T polymorphism affected persistence in the CFS patients. The concept of persistence has been linked to specific personality, such as perfectionism, in CFS. SIGNIFICANCE: Our results suggest that the biosynthetic pathways of the monoamine neurotransmitters that are mediated by TH and GCH might be associated with the CFS clinical findings, because persistence is one of the typical personality traits observed in CFS and patients with major depressive disorder exhibit a higher harm avoidance score.

  Feb. 2013, Life sciences, 92(3) (3), 183 - 6, English, International magazine

  Scientific journal


• Two different types of mental fatigue produce different styles of task performance

  Yoshihito Shigihara, Masaaki Tanaka, Akira Ishii, Seiki Tajima, Etsuko Kanai, Masami Funakura, Yasuyoshi Watanabe

  Feb. 2013, Neurology Psychiatry and Brain Research, 19(1) (1), 5 - 11, English

  [Refereed]

  Scientific journal


• Evaluation of breast cancer resistance protein function in hepatobiliary and renal excretion using PET with 11C-SC-62807.

  Tadayuki Takashima, Chunyong Wu, Misato Takashima-Hirano, Yumiko Katayama, Yasuhiro Wada, Masaaki Suzuki, Hiroyuki Kusuhara, Yuichi Sugiyama, Yasuyoshi Watanabe

  UNLABELLED: A quantitative PET imaging method was used to assess the in vivo kinetics of hepatobiliary and renal excretion of the breast cancer resistance protein (Bcrp) substrate (11)C-SC-62807 in mice. METHODS: Serial abdominal PET scans were collected in wild-type and Bcrp knockout (Bcrp(-/-)) mice after intravenous injection of (11)C-SC-62807. Venous blood samples and PET images were obtained at frequent intervals up to 30 min after radiotracer administration. Dynamic PET data were analyzed to determine the canalicular and brush-border efflux clearances in the liver and kidney (CL(int,bile,liver) and CL(int,urine,kidney), respectively). RESULTS: SC-62807 is an in vitro substrate of mouse Bcrp and human BCRP. Radioactivity associated with (11)C-SC-62807 was predominantly found in the blood, liver, bile, and urine 30 min after administration. Both biliary and urinary excretion of radioactivity was markedly lower in Bcrp(-/-) mice than in wild-type mice, suggesting greater systemic exposure in Bcrp(-/-) mice. Both the CL(int,bile,liver) and the CL(int,urine,kidney) were significantly lower in Bcrp(-/-) mice (74% ± 10% and 99% ± 1% lower than controls, respectively). We also found that (11)C-SC-62807 is a substrate of the organic anion-transporting polypeptides OATP1B1 and OATP1B3 in vitro. CONCLUSION: The present study demonstrated that Bcrp plays a significant role in the efflux of (11)C-SC-62807 in mouse liver and kidney. We also demonstrated the feasibility of PET using (11)C-SC-62807 to study the activity of BCRP in humans.

  Feb. 2013, Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 54(2) (2), 267 - 76, English, International magazine

  Scientific journal


• Kinetics of neurodegeneration based on a risk-related biomarker in animal model of glaucoma.

  Takuya Hayashi, Masamitsu Shimazawa, Hiroshi Watabe, Takayuki Ose, Yuta Inokuchi, Yasushi Ito, Hajime Yamanaka, Shin-ichi Urayama, Yasuyoshi Watanabe, Hideaki Hara, Hirotaka Onoe

  BACKGROUND: Neurodegenerative diseases including Parkinson's and Alzheimer's diseases progress slowly and steadily over years or decades. They show significant between-subject variation in progress and clinical symptoms, which makes it difficult to predict the course of long-term disease progression with or without treatments. Recent technical advances in biomarkers have facilitated earlier, preclinical diagnoses of neurodegeneration by measuring or imaging molecules linked to pathogenesis. However, there is no established "biomarker model" by which one can quantitatively predict the progress of neurodegeneration. Here, we show predictability of a model with risk-based kinetics of neurodegeneration, whereby neurodegeneration proceeds as probabilistic events depending on the risk. RESULTS: We used five experimental glaucomatous animals, known for causality between the increased intraocular pressure (IOP) and neurodegeneration of visual pathways, and repeatedly measured IOP as well as white matter integrity by diffusion tensor imaging (DTI) as a biomarker of axonal degeneration. The IOP in the glaucomatous eye was significantly increased than in normal and was varied across time and animals; thus we tested whether this measurement is useful to predict kinetics of the integrity. Among four kinds of models of neurodegeneration, constant-rate, constant-risk, variable-risk and heterogeneity models, goodness of fit of the model and F-test for model selection showed that the time course of optic nerve integrity was best explained by the variable-risk model, wherein neurodegeneration kinetics is expressed in an exponential function across cumulative risk based on measured IOP. The heterogeneity model with stretched exponential decay function also fit well to the data, but without statistical superiority to the variable-risk model. The variable-risk model also predicted the number of viable axons in the optic nerve, as assessed by immunohistochemistry, which was also confirmed to be correlated with the pre-mortem integrity of the optic nerve. In addition, the variable-risk model identified the disintegrity in the higher-order visual pathways, known to underlie the transsynaptic degeneration in this disease. CONCLUSIONS: These findings indicate that the variable-risk model, using a risk-related biomarker, could predict the spatiotemporal progression of neurodegeneration. This model, virtually equivalent to survival analysis, may allow us to estimate possible effect of neuroprotection in delaying progress of neurodegeneration.

  Jan. 2013, Molecular neurodegeneration, 8, 4 - 4, English, International magazine

  Scientific journal


• Two types of mental fatigue affect spontaneous oscillatory brain activities in different ways.

  Yoshihito Shigihara, Masaaki Tanaka, Akira Ishii, Etsuko Kanai, Masami Funakura, Yasuyoshi Watanabe

  BACKGROUND: Fatigue has a multi-factorial nature. We examined the effects of two types of mental fatigue on spontaneous oscillatory brain activity using magnetoencephalography (MEG). METHODS: Participants were randomly assigned to two groups in a single-blinded, crossover fashion to perform two types of mental fatigue-inducing experiments. Each experiment consisted of a 30-min fatigue-inducing 0- or 2-back test session and two evaluation sessions performed just before and after the fatigue-inducing mental task session. RESULTS: After the 0-back test, decreased alpha power was indicated in the right angular gyrus and increased levels in the left middle and superior temporal gyrus, left postcentral gyrus, right superior frontal gyrus, left inferior frontal gyrus, and right medial frontal gyrus. After the 2-back test, decreased alpha power was indicated in the right middle and superior frontal gyrus and increased levels in the left inferior parietal and superior parietal lobules, right parahippocampal gyrus, right uncus, left postcentral gyrus, left middle frontal gyrus, and right inferior frontal gyrus. For beta power, increased power following the 0-back test was indicated in the left middle temporal gyrus, left superior frontal gyrus, left cingulate gyrus, and left precentral gyrus. After the 2-back test, decreased power was suggested in the left superior frontal gyrus and increased levels in the left middle temporal gyrus and left inferior parietal lobule. Some of these brain regions might be associated with task performance during the fatigue-inducing trials. CONCLUSIONS: Two types of mental fatigue may produce different alterations of the spontaneous oscillatory MEG activities. Our findings would provide new perspectives on the neural mechanisms underlying mental fatigue.

  Jan. 2013, Behavioral and brain functions : BBF, 9, 2 - 2, English, International magazine

  Scientific journal


• Neural dysfunction in chronic fatigue syndrome

  Masaaki Tanaka, Akira Ishii, Yasuyoshi Watanabe

  I O S Press, 2013, Advances in Neuroimmune Biology, 4(4) (4), 291 - 300, English

  [Refereed]

  Scientific journal


• [Molecular imaging-based early-phase and exploratory clinical research].

  Yasuyoshi Watanabe

  In vivo molecular imaging became a key technology for innovative drug development. Especially, positron emission tomography (PET) has been applied to patho-physiological science, pharmacodynamics/pharmacokinetics (PD/PK) studies, and drug delivery system (DDS) studies, and accelerated the paradigm shift not only from experimental animals to human subjects, but also from PK in blood circulation to PK in target tissues, even in human. Our RIKEN Centre for Molecular Imaging Science has been established to promote such innovative drug developmental studies with PET molecular imaging, as a center of excellence for development of molecular probes. The center is creating novel labeling methods on drug candidate molecules with positron-emitting radionuclides, and is providing the molecular probes suitable for targeting bio-functional molecules and cellular functions, which are useful for evaluation of drug efficacy and pharmacokinetics in human subjects. Animal PET studies with mice, rats, rabbits, marmosets, and macaque monkeys have also been promoted both under anesthetic condition and consciousness, which was a really difficult task but important for comparison with human PET studies. In this sense, mutual collaboration between the research consortia in basic PET field and in clinical PET molecular imaging such as Osaka City University Hospital would be of great value. Here, the concept, outline of our activities, and PK/PD studies with efficient application of molecular imaging is presented. In addition, the results of the first cassette-dose and micro-dose clinical trials approved by Pharmaceuticals and Medical Devices Agency (PMDA) (New Energy and Industrial Technology Development Organization (NEDO) project represented by Prof. Yuichi Sugiyama) are described.

  2013, Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan, 133(2) (2), 187 - 95, Japanese, Domestic magazine

  Scientific journal


• Fatigue-recovering effect of a house designed with open space.

  Masaaki Tanaka, Hiromi Yamada, Takayuki Nakamura, Akira Ishii, Yasuyoshi Watanabe

  CONTEXT: Exposure to a natural environment has been reported to be associated with positive effects on mental well-being. However, no report has examined the effects of a house designed with an open space connected to nature on recovery from fatigue. OBJECTIVE: The purpose of this study was to examine the effects of such an open space on recovery from mental fatigue. DESIGN: Placebo-controlled, crossover design. SETTING: Participants were randomized into open (connected to nature) and closed (not connected to nature) conditions. PARTICIPANTS: Sixteen healthy female volunteers were enrolled. INTERVENTION: After a 30-minute fatigue-inducing mental task, participants moved to an open or closed recovery room for 30 minutes. MAIN OUTCOME MEASURES: As fatigue-evaluating mental tasks, participants performed advanced trail making tests for 20 minutes. They were asked to rate their levels of fatigue, relaxation, comfort, and healing on a visual analogue scale from 0 (minimum) to 100 (maximum) to evaluate their subjective mental. They also underwent accelerated plethysmography. RESULTS: After the recovery session, lower total error counts of a cognitive test, greater levels of subjective relaxation, comfort, and healing, and lower levels of waveform index-1 assessed via accelerated plethysmography were observed in participants exposed to the open condition compared with the closed condition. These results provide evidence that the use of a house designed with an open space connected to nature during the recovery session improved cognitive function and subjective mental states. Hence, open space was effective for helping recovery from mental fatigue.

  2013, Explore (New York, N.Y.), 9(2) (2), 82 - 6, English, International magazine

  Scientific journal


• Novel molecular imaging of atherosclerosis with gallium-68-labeled apolipoprotein A-I mimetic peptide and positron emission tomography.

  Emi Kawachi, Yoshinari Uehara, Koki Hasegawa, Eiji Yahiro, Setsuko Ando, Yasuhiro Wada, Tsuneo Yano, Hiroaki Nishikawa, Masashi Shiomi, Shin-ichiro Miura, Yasuyoshi Watanabe, Keijiro Saku

  BACKGROUND:  High-density lipoprotein (HDL) plays a major role in reverse cholesterol transport. Many researchers have been working to enhance the biochemical function of HDL for use in therapy. Although HDL therapy using injections of apolipoprotein (apo)-A-I mimetics, apo A-I Milano or full-length apo A-I is dramatically effective, it is still unclear whether apo A-I or apo A-I mimetics actually enter atherosclerotic plaque and remove cholesterol from the lipid burden. We synthesized a novel 24-amino acid apo A-I mimetic peptide (known as FAMP) that potently removes cholesterol via specific ATP-binding cassette transporter A1. We then investigated the potential of FAMP to image developing plaque lesions in vivo. METHODS AND RESULTS:  FAMP was modified with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and radiolabeled with gallium-68 ((68)Ga) for noninvasive positron emission tomography (PET) in an animal model (familial hypercholesterolemic myocardial infarction-prone rabbits: WHHL-MI) with atherosclerotic lesions. The (68)Ga-DOTA-FAMP was dramatically taken up by atherosclerotic tissues in the blood vessels and aorta of WHHL-MI rabbits, but not the control rabbits. CONCLUSIONS:  An apo A-I mimetic peptide with (68)Ga-DOTA is a promising candidate diagnostic tracer for PET imaging of the atherosclerotic lipid burden and may contribute to the development of a tool for the diagnosis of plaque with PET.

  2013, Circulation journal : official journal of the Japanese Circulation Society, 77(6) (6), 1482 - 9, English, Domestic magazine

  Scientific journal


• Neurocognitive impairment in childhood chronic fatigue syndrome.

  Kei Mizuno, Yasuyoshi Watanabe

  Neurocognitive impairment is a feature of childhood chronic fatigue syndrome (CCFS). Several studies have demonstrated reduced attention control in CCFS patients in switching and divided attention tasks. In students, the extent of deterioration in task performance depends on the level of fatigue. Poor performance in switching and divided attention is common in both fatigued students and CCFS patients. Additionally, attentional functions show dramatic development from childhood to adolescence, suggesting that abnormal development of switching and divided attention may be induced by chronic fatigue. The brain structures associated with attentional control are situated in the frontal and parietal cortices, which are the last to mature, suggesting that severe fatigue in CCFS patients and students may inhibit normal structural and functional development in these regions. A combination of treatment with cognitive behavioral therapy and antidepressant medication is effective to improve attentional control processing in CCFS patients. Studies identifying the features of neurocognitive impairment in CCFS have improved our current understanding of the neurophysiological mechanisms of CCFS.

  2013, Frontiers in physiology, 4, 87 - 87, English, International magazine

  Scientific journal


• Neural correlates of central inhibition during physical fatigue.

  Masaaki Tanaka, Akira Ishii, Yasuyoshi Watanabe

  Central inhibition plays a pivotal role in determining physical performance during physical fatigue. Classical conditioning of central inhibition is believed to be associated with the pathophysiology of chronic fatigue. We tried to determine whether classical conditioning of central inhibition can really occur and to clarify the neural mechanisms of central inhibition related to classical conditioning during physical fatigue using magnetoencephalography (MEG). Eight right-handed volunteers participated in this study. We used metronome sounds as conditioned stimuli and maximum handgrip trials as unconditioned stimuli to cause central inhibition. Participants underwent MEG recording during imagery of maximum grips of the right hand guided by metronome sounds for 10 min. Thereafter, fatigue-inducing maximum handgrip trials were performed for 10 min; the metronome sounds were started 5 min after the beginning of the handgrip trials. The next day, neural activities during imagery of maximum grips of the right hand guided by metronome sounds were measured for 10 min. Levels of fatigue sensation and sympathetic nerve activity on the second day were significantly higher relative to those of the first day. Equivalent current dipoles (ECDs) in the posterior cingulated cortex (PCC), with latencies of approximately 460 ms, were observed in all the participants on the second day, although ECDs were not identified in any of the participants on the first day. We demonstrated that classical conditioning of central inhibition can occur and that the PCC is involved in the neural substrates of central inhibition related to classical conditioning during physical fatigue.

  2013, PloS one, 8(7) (7), e70949, English, International magazine

  Scientific journal


• Neural mechanisms underlying chronic fatigue.

  Masaaki Tanaka, Akira Ishii, Yasuyoshi Watanabe

  Fatigue is defined as a condition or phenomenon of declined ability and efficiency of mental and/or physical activities, caused by excessive mental or physical activities, diseases, or syndromes. Acute fatigue is a normal condition that disappears after a period of rest; in contrast, chronic fatigue does not disappear after an ordinary rest. Chronic fatigue impairs daily activities and contributes to various medical conditions and death. In addition, many people complain of chronic fatigue. It would thus be of great value to clarify the mechanisms underlying chronic fatigue and to develop efficient treatment methods to overcome it. Here, we review data primarily from behavioral, neurophysiological, and neuroimaging experiments related to the neural mechanisms underlying chronic fatigue. We propose that repetitive and prolonged overwork and/or stress cause neural damage of a facilitation system, as well as central sensitization and classical conditioning of an inhibition system. We also propose a new treatment strategy for chronic fatigue on the basis of its underlying neural mechanisms.

  2013, Reviews in the neurosciences, 24(6) (6), 617 - 28, English, International magazine

  Scientific journal


• Osmotic release oral system-methylphenidate improves neural activity during low reward processing in children and adolescents with attention-deficit/hyperactivity disorder.

  Kei Mizuno, Tetsuya Yoneda, Masanori Komi, Toshinori Hirai, Yasuyoshi Watanabe, Akemi Tomoda

  Attention-deficit/hyperactivity disorder (ADHD) is neurobehavioral disorder characterized by inattention, hyperactivity/impulsivity and impaired reward system function, such as delay aversion and low reward sensitivity. The pharmacological treatment for ADHD includes methylphenidate (MPH), or osmotic release oral system-MPH (OROS-MPH), which increases extrasynaptic dopamine and noradrenaline levels by blocking their reuptake. Although previous functional magnetic resonance imaging (fMRI) studies revealed that acute treatment with MPH alters activation of the nucleus accumbens during delay aversion in children and adolescents with ADHD, the effects a relatively long period of OROS-MPH treatment on delay aversion as well as reward sensitivity remain unclear. Thus, we evaluated brain activation with fMRI during a reward sensitivity paradigm that consists of high monetary reward and low monetary reward conditions before and after a 3-month treatment with OROS-MPH in 17 children and adolescents with ADHD (mean age, 13.3 ± 2.2) and 17 age- and sex-matched healthy controls (mean age, 13.0 ± 1.9). We found that before treatment there was decreased activation of the nucleus accumbens and thalamus in patients with ADHD during only the low monetary reward condition, which was improved to same level as those of the healthy controls after the treatment. The observed change in brain activity was associated with improved ADHD symptom scores, which were derived from Japanese versions of the ADHD rating scale-IV. These results suggest that treatment with OROS-MPH for a relatively long period is effective in controlling reward sensitivity in children and adolescents with ADHD.

  2013, NeuroImage. Clinical, 2, 366 - 76, English, International magazine

  Scientific journal


• Neural mechanism of facilitation system during physical fatigue.

  Masaaki Tanaka, Akira Ishii, Yasuyoshi Watanabe

  An enhanced facilitation system caused by motivational input plays an important role in supporting performance during physical fatigue. We tried to clarify the neural mechanisms of the facilitation system during physical fatigue using magnetoencephalography (MEG) and a classical conditioning technique. Twelve right-handed volunteers participated in this study. Participants underwent MEG recording during the imagery of maximum grips of the right hand guided by metronome sounds for 10 min. Thereafter, fatigue-inducing maximum handgrip trials were performed for 10 min; the metronome sounds were started 5 min after the beginning of the handgrip trials. The metronome sounds were used as conditioned stimuli and maximum handgrip trials as unconditioned stimuli. The next day, they were randomly assigned to two groups in a single-blinded, two-crossover fashion to undergo two types of MEG recordings, that is, for the control and motivation sessions, during the imagery of maximum grips of the right hand guided by metronome sounds for 10 min. The alpha-band event-related desynchronizations (ERDs) of the motivation session relative to the control session within the time windows of 500 to 700 and 800 to 900 ms after the onset of handgrip cue sounds were identified in the sensorimotor areas. In addition, the alpha-band ERD within the time window of 400 to 500 ms was identified in the right dorsolateral prefrontal cortex (Brodmann's area 46). The ERD level in the right dorsolateral prefrontal cortex was positively associated with that in the sensorimotor areas within the time window of 500 to 700 ms. These results suggest that the right dorsolateral prefrontal cortex is involved in the neural substrates of the facilitation system and activates the sensorimotor areas during physical fatigue.

  2013, PloS one, 8(11) (11), e80731, English, International magazine

  Scientific journal


• 8.PETを用いた体内動態研究のためのチアミンとフルスルチアミンの^<11>C標識合成(第431回研究協議会研究発表要旨,ビタミンB研究委員会)

  土居 久志, 馬渡 彩, 金澤 奨勝, 野崎 聡, 中谷 友香, 野村 之博, 秋元 浩二, 二宮 伸二, 鈴木 正昭, 渡辺 恭良

  公益社団法人 日本ビタミン学会, 2013, ビタミン, 87(5) (5), 290 - 290, Japanese


• Cognitive dysfunction in elderly females with depressive symptoms.

  Masaaki Tanaka, Akira Ishii, Emi Yamano, Hiroki Ogikubo, Masatsugu Okazaki, Kazuro Kamimura, Yasuharu Konishi, Shigeru Emoto, Yasuyoshi Watanabe

  BACKGROUND: A depressive state is a common symptom in the elderly and often accompanies cognitive impairment. The coexistence of depressive symptoms and cognitive impairment is a serious problem, as it increases adverse outcomes for health, functional status, and mortality. It would thus be of great value to clarify the cognitive dysfunction associated with depressive symptoms. We aimed to identify the cognitive dysfunction, in particular, impairment of the response inhibition component of executive function, associated with depressive symptoms in elderly females using the Simple Color Reaction Test and Modified Stroop Color-Word Test. MATERIAL/METHODS: The study group consisted of 35 elderly women. They performed cognitive function task trials for 9 min. Univariate logistic regression analyses were performed to identify factors associated with the prevalence of the depressive state. RESULTS: Longer reaction time and lower correction rate of response inhibition trials were related to the prevalence of the depressive symptoms. CONCLUSIONS: Impaired function of response inhibition may be a specific feature of the depressive state. Our findings may help clarify the neural mechanisms underlying the depressive state of elderly females.

  Dec. 2012, Medical science monitor : international medical journal of experimental and clinical research, 18(12) (12), CR706-11, English, International magazine

  Scientific journal


• Uniformly cationized protein efficiently reaches the cytosol of mammalian cells.

  Midori Futami, Yasuyoshi Watanabe, Takashi Asama, Hitoshi Murata, Hiroko Tada, Megumi Kosaka, Hidenori Yamada, Junichiro Futami

  Protein cationization techniques are powerful protein transduction methods for mammalian cells. As we demonstrated previously, cationized proteins with limited conjugation to polyethylenimine have excellent ability to enter into cells by adsorption-mediated endocytosis [Futami, J., et al. (2005) J. Biosci. Bioeng. 99, 95-103]. In this study, we show that proteins with extensive and uniform cationization covering the protein surface reach the cytoplasm and nucleus more effectively than proteins with limited cationic polymers or proteins that are fused to cationic peptides. Although extensive modification of carboxylates results in loss of protein function, chicken avidin retains biotin-binding ability even after extensive amidation of carboxylates. Using this cationized avidin carrier system, the protein transduction ability of variously cationized avidins was investigated using biotinylated protein as a probe. The results revealed that cationized avidins bind rapidly to the cell surface followed by endocytotic uptake. Small amounts of uniformly cationized avidin showed direct penetration into the cytoplasm within a 15 min incubation. This penetration route seemed to be energy dependent and functioned under cellular physiological conditions. A biotinylated exogenous transcription factor protein that penetrated cells was demonstrated to induce target gene expression in living cells.

  Oct. 2012, Bioconjugate chemistry, 23(10) (10), 2025 - 31, English, International magazine

  Scientific journal


• Risk-management syndrome.

  Masaaki Tanaka, Yasuyoshi Watanabe

  OBJECTIVE AND METHODS: In order to survive, organisms must pursue and capture prey to avoid starvation, and must either fight or flight to avoid being killed by predators. The starvation-resistance and risk-management systems were of great importance to humans for survival in ancient times. However, given the evolutionary time scale, humans seem not to be well adapted to modern times. Urbanization often puts the risk-management system in motion due to modern stressors, and can induce over-activation of the risk-management system. RESULTS: As a result, central sensitization and classical conditioning of the over-risk-management can occur due to repeated assaults, fears, or even anticipation of the modern predators. We refer to those diseases as risk-management syndrome, defined as an illness caused by the central sensitization and classical conditioning of over-risk-management without apparent organic damage. CONCLUSION: These syndromes classified by each pathophysiological background, i.e. risk-management and metabolic syndromes are two major syndromes associated with urbanization.

  Oct. 2012, International journal of psychiatry in clinical practice, 16(4) (4), 312 - 5, English, International magazine

  Scientific journal


• New findings on the underlying neural mechanism of emotion induced by frightening music.

  Yasuyoshi Watanabe

  Oct. 2012, Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 53(10) (10), 1497 - 8, English, International magazine

  Scientific journal


• Effect of mental fatigue on the central nervous system: an electroencephalography study.

  Masaaki Tanaka, Yoshihito Shigihara, Akira Ishii, Masami Funakura, Etsuko Kanai, Yasuyoshi Watanabe

  BACKGROUND: Fatigue can be classified as mental and physical depending on its cause, and each type of fatigue has a multi-factorial nature. We examined the effect of mental fatigue on the central nervous system using electroencephalography (EEG) in eighteen healthy male volunteers. METHODS: After enrollment, subjects were randomly assigned to two groups in a single-blinded, crossover fashion to perform two types of mental fatigue-inducing experiments. Each experiment consisted of four 30-min fatigue-inducing 0- or 2-back test sessions and two evaluation sessions performed just before and after the fatigue-inducing sessions. During the evaluation session, the participants were assessed using EEG. Eleven electrodes were attached to the head skin, from positions F3, Fz, F4, C3, Cz, C4, P3, Pz, P4, O1, and O2. RESULTS: In the 2-back test, the beta power density on the Pz electrode and the alpha power densities on the P3 and O2 electrodes were decreased, and the theta power density on the Cz electrode was increased after the fatigue-inducing mental task sessions. In the 0-back test, no electrodes were altered after the fatigue-inducing sessions. CONCLUSIONS: Different types of mental fatigue produced different kinds of alterations of the spontaneous EEG variables. Our findings provide new perspectives on the neural mechanisms underlying mental fatigue.

  Sep. 2012, Behavioral and brain functions : BBF, 8, 48 - 48, English, International magazine

  Scientific journal


• 19 Template-Assisted Transcription Synthesis of Phosphorylated Protein Recognition Peptide and Its Selective Tumor Growth Inhibition(Oral Presentation)

  Tanaka Katsunori, Iwata Takayuki, Shirotsuki Sanae, Kageyama Chika, Tahara Tsuyoshi, Nozaki Satoshi, Siwu Eric R.O., Tamura Satoru, Douke Shunsuke, Murakami Nobutoshi, Onoe Hirotaka, Watanabe Yasuyoshi, Fukase Koichi

  Exploring efficient strategies for identifying the natural products and their derivatives that selectively regulate protein/protein interactions is one of the most actively studied topics in chemical biology. Especially, the selective activation and/or inhibition of specific phosphorylation-mediated protein/protein interactions within a signaling pathway may direct a specific biological response on the cellular level. In pursuit of such molecules, we developed a Template-Assisted Transcription Synthesis. The approach is based on our findings that (i) the bis-lysine structure such as 1 interacts with the phosphorylated compounds, and (ii) the benzyl-protected histidine significantly accelerates the peptide-based Huisgen cycloaddition, so that the structure 1 can efficiently be modified by the peptide library to strongly and selectively bind to the target phosphorylated protein in a template-assisted fashion. As a model case, we applied to preparing the Grb2/SH2 domain mimicry. The template-assisted transcription synthesis between the bis-lysine 1 and the acetylene-peptide library 2 was performed in the presence of the cyclic phosphopeptide 3 (known ligand for Grb2/SH2 domain) as the template. The clicked peptides 4a, b, and c as the template-assisted products, exhibited the micromolar-level dissociation constants to the phosphopeptide 3. Conformational restriction of the initial hit structure 4a by the solid-supported ring-closing metathesis gave the cyclic peptide 9, further enhancing the interaction with the peptide 3, i.e., Kd of 590 nM. One of the clicked product 4a, the peptidyl mimic of the Grb2-SH2 domain, was found to be internalized into A431 cancer cells, where the EGFR-induced cellular signalling is operative. It selectively bound to the phosphorylated Shc protein, one of the Grb2-SH2 interacting signaling proteins, induced A431-selective apoptosis and tumor growth inhibition. The clicked peptide 4a even exhibited the A431-selective inhibition of tumor growth without any toxic effects and inflammatory responses in the preliminary animal experiments. The results described in this symposium demonstrate the tailor-made synthesis of artificial receptors using a Template-Assisted Transcription Synthesis that is clearly distinct from previous methods. This approach may efficiently and rapidly provide small-molecular regulators that selectively control a specific cell signaling pathway or protein/protein interactions.

  Symposium on the chemistry of natural products, Sep. 2012, Symposium on the Chemistry of Natural Products, symposium papers, (54) (54), 109 - 114, Japanese


• Dynamic analysis of GI absorption and hepatic distribution processes of telmisartan in rats using positron emission tomography.

  Makoto Kataoka, Tadayuki Takashima, Tomotaka Shingaki, Yoshinobu Hashidzume, Yumiko Katayama, Yasuhiro Wada, Hiroyuki Oh, Yoshie Masaoka, Shinji Sakuma, Yuichi Sugiyama, Shinji Yamashita, Yasuyoshi Watanabe

  PURPOSE: To dynamically analyze the processes of oral absorption and hepatobiliary distribution of telmisartan using positron emission tomography (PET). METHODS: (11)C-labeled telmisartan ([(11)C]TEL) was orally administered to rats with or without non-radiolabeled telmisartan (0.5, and 10 mg/kg). PET scanning of abdominal region and whole body was performed under conscious condition. In situ intestinal closed loop study in rats and in vitro permeation study in MDR1-MDCK II cell monolayers were also conducted. RESULTS: After oral administration of [(11)C]TEL, systemic bioavailability and hepatic distribution of radioactivity increased non-linearly with dose. In the intestinal lumen, both telmisartan and its glucuronide were detected and the ratio of telmisartan decreased dramatically at high dose of telmisartan. In situ closed loop study showed most of telmisartan-glucuronide detected in the intestinal lumen was derived from the bile excretion. In addition, in vitro permeation study revealed that telmisartan is a substrate of P-glycoprotein. CONCLUSION: PET imaging analysis successfully demonstrated the processes of intestinal absorption and hepatic distribution of telmisartan. PET study combined with appropriate in situ and in vitro experiments is highly expected to be a potent tool for better understanding of GI absorption and subsequent tissue distribution of various drugs and drug candidates.

  Sep. 2012, Pharmaceutical research, 29(9) (9), 2419 - 31, English, International magazine

  Scientific journal


• Increase of 20-HETE synthase after brain ischemia in rats revealed by PET study with 11C-labeled 20-HETE synthase-specific inhibitor.

  Toshiyuki Kawasaki, Toshiyuki Marumo, Keiko Shirakami, Tomoko Mori, Hisashi Doi, Masaaki Suzuki, Yasuyoshi Watanabe, Shigeyuki Chaki, Atsuro Nakazato, Yukio Ago, Hitoshi Hashimoto, Toshio Matsuda, Akemichi Baba, Hirotaka Onoe

  20-Hydroxyeicosatetraenoic acid (20-HETE), an arachidonic acid metabolite known to be produced after cerebral ischemia, has been implicated in ischemic and reperfusion injury by mediating vasoconstriction. To develop a positron emission tomography (PET) probe for 20-HETE synthase imaging, which might be useful for monitoring vasoconstrictive processes in patients with brain ischemia, we synthesized a (11)C-labeled specific 20-HETE synthase inhibitor, N'(4-dimethylaminohexyloxy)phenyl imidazole ([(11)C]TROA). Autoradiographic study showed that [(11)C]TROA has high-specific binding in the kidney and liver consistent with the previously reported distribution of 20-HETE synthase. Using transient middle cerebral artery occlusion in rats, PET study showed significant increases in the binding of [(11)C]TROA in the ipsilateral hemisphere of rat brains after 7 and 10 days, which was blocked by co-injection of excess amounts of TROA (10 mg/kg). The increased [(11)C]TROA binding on the ipsilateral side returned to basal levels within 14 days. In addition, quantitative real-time PCR revealed that increased expression of 20-HETE synthase was only shown on the ipsilateral side on day 7. These results indicate that [(11)C]TROA might be a useful PET probe for imaging of 20-HETE synthase in patients with cerebral ischemia.

  Sep. 2012, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 32(9) (9), 1737 - 46, English, International magazine

  Scientific journal


• Effect of a human-type communication robot on cognitive function in elderly women living alone.

  Masaaki Tanaka, Akira Ishii, Emi Yamano, Hiroki Ogikubo, Masatsugu Okazaki, Kazuro Kamimura, Yasuharu Konishi, Shigeru Emoto, Yasuyoshi Watanabe

  BACKGROUND: Considering the high prevalence of dementia, it would be of great value to develop effective tools to improve cognitive function. We examined the effects of a human-type communication robot on cognitive function in elderly women living alone. MATERIAL/METHODS: In this study, 34 healthy elderly female volunteers living alone were randomized to living with either a communication robot or a control robot at home for 8 weeks. The shape, voice, and motion features of the communication robot resemble those of a 3-year-old boy, while the control robot was not designed to talk or nod. Before living with the robot and 4 and 8 weeks after living with the robot, experiments were conducted to evaluate a variety of cognitive functions as well as saliva cortisol, sleep, and subjective fatigue, motivation, and healing. RESULTS: The Mini-Mental State Examination score, judgement, and verbal memory function were improved after living with the communication robot; those functions were not altered with the control robot. In addition, the saliva cortisol level was decreased, nocturnal sleeping hours tended to increase, and difficulty in maintaining sleep tended to decrease with the communication robot, although alterations were not shown with the control. The proportions of the participants in whom effects on attenuation of fatigue, enhancement of motivation, and healing could be recognized were higher in the communication robot group relative to the control group. CONCLUSIONS: This study demonstrates that living with a human-type communication robot may be effective for improving cognitive functions in elderly women living alone.

  Sep. 2012, Medical science monitor : international medical journal of experimental and clinical research, 18(9) (9), CR550-7, English, International magazine

  Scientific journal


• Whole-body distribution and radiation dosimetry of [11C]telmisartan as a biomarker for hepatic organic anion transporting polypeptide (OATP) 1B3.

  Keiji Shimizu, Tadayuki Takashima, Tomohiko Yamane, Masahiro Sasaki, Hiromitsu Kageyama, Yoshinobu Hashizume, Kazuya Maeda, Yuichi Sugiyama, Yasuyoshi Watanabe, Michio Senda

  INTRODUCTION: Telmisartan, a nonpeptide angiotensin II AT1 receptor antagonist used as an antihypertensive drug, is specifically taken up by the liver through the OATP1B3. PET imaging with [(11)C]telmisartan is expected to provide information about the whole body pharmacokinetics of telmisartan as well as its transport property by OATP1B3. The purpose of the study was to determine the biodistribution and radiation dosimetry of [(11)C]telmisartan in humans. METHODS: Biodistribution of [(11)C]telmisartan was measured in three rats and six healthy male human volunteers. In the rat study, a dynamic emission scan was performed for 90 min. In the human study, dynamic whole-body PET images were acquired after intravenous injection of [(11)C]telmisartan. ROIs were defined for source organs on the PET images to measure time-course of [(11)C]telmisartan uptake as percentage injected dose and the number of disintegration for each organ. Radiation dosimetry was calculated with OLINDA/EXM. RESULTS: In the rat study, most radioactivity was rapidly taken up by the liver and part of it was excreted into the biliary tract and intestine. Extrapolating from the rat data, the effective dose for the adult human being was estimated to be 3.65±0.01 microSv/MBq (n=3). In the human study, most of the tracer was taken up by the liver as well, although not as rapidly as in the rat. The activity in the gall bladder and intestine increased gradually. The effective dose for the adult human being was 4.24±0.09 microSv/MBq (n=6). CONCLUSIONS: [(11)C]Telmisartan is a safe PET tracer with a dosimetry profile comparable to other common (11)C PET tracers.

  Aug. 2012, Nuclear medicine and biology, 39(6) (6), 847 - 53, English, International magazine

  Scientific journal


• Validation of the Japanese version of the power of food scale in a young adult population.

  Takahiro Yoshikawa, Keisuke Orita, Yasuyoshi Watanabe, Masaaki Tanaka

  Aug. 2012, Psychological reports, 111(1) (1), 253 - 65, English, International magazine

  Scientific journal


• 放射性ソマトスタチンアナログを用いた2型糖尿病モデルラットの膵内分泌細胞PETイメージング

  佐古 健生, 長谷川 功紀, 崔 翼龍, 和田 康弘, 林中 恵美, 片岡 洋祐, 千田 道雄, 渡辺 恭良

  (一社)日本核医学会, Aug. 2012, 核医学, 49(3) (3), S255 - S255, Japanese


• Quantification of regional cerebral blood flow in rats using an arteriovenous shunt and micro-PET.

  Takayuki Ose, Hiroshi Watabe, Takuya Hayashi, Nobuyuki Kudomi, Masaaki Hikake, Hajime Fukuda, Noboru Teramoto, Yasuyoshi Watanabe, Hirotaka Onoe, Hidehiro Iida

  INTRODUCTION: Measurement of regional cerebral blood flow (rCBF) in rodents can provide knowledge of pathophysiology of the cerebral circulation, but generally requires blood sampling for analysis during positron emission tomography (PET). We therefore tested the feasibility of using an arteriovenous (AV) shunt in rats for less invasive blood analysis. METHODS: Six anesthetized rats received [15O]H2O and [15O]CO PET scans with their femoral artery and vein connected by an AV shunt, the activity within which was measured with a germanium ortho-oxysilicate scintillation detector. The [15O]H2O was intravenously injected either at a faster or slower injection rate, while animals were placed either with their head or heart centered in the gantry. The time-activity curve (TAC) from the AV shunt was compared with that from the cardiac ventricle in PET image. The rCBF values were calculated by a nonlinear least-square method using the dispersion-corrected AV-shunt TAC as an input. RESULTS: The AV-shunt TAC had higher signal-to-noise ratio, but also had delay and dispersion compared with the image-derived TAC. The delay time between the AV-shunt TAC and image-based TAC ranged from 11 to 21 s, while the dispersion was estimated to be ∼5 s as a time constant of the dispersion model of exponential function, and both were properly corrected. In a steady-state condition of [15O]CO PET, the blood activity concentration by AV-shunt TAC was also comparable in height with the image-based TAC corrected for partial volume. Whole-brain CBF values measured by [15O]H2O were 0.37±0.04 (mean±S.D.) ml/g/min, partition coefficient was 0.73±0.04 ml/g, and the CBF varied in a linear relationship with partial pressure of carbon dioxide during each scan. CONCLUSIONS: The AV-shunt technique allows less invasive, quantitative and reproducible measurement of rCBF in [15O]H2O PET studies in rats than direct blood sampling and radioassay.

  Jul. 2012, Nuclear medicine and biology, 39(5) (5), 730 - 41, English, International magazine

  Scientific journal


• The neural substrates associated with attentional resources and difficulty of concurrent processing of the two verbal tasks.

  Kei Mizuno, Masaaki Tanaka, Hiroki C Tanabe, Norihiro Sadato, Yasuyoshi Watanabe

  The kana pick-out test has been widely used in Japan to evaluate the ability to divide attention in both adult and pediatric patients. However, the neural substrates underlying the ability to divide attention using the kana pick-out test, which requires participants to pick out individual letters (vowels) in a story while also reading for comprehension, thus requiring simultaneous allocation of attention to both activities, are still unclear. Moreover, outside of the clinical area, neuroimaging studies focused on the mechanisms of divided attention during complex story comprehension are rare. Thus, the purpose of the present study, to clarify the neural substrates of kana pick-out test, improves our current understanding of the basic neural mechanisms of dual task performance in verbal memory function. We compared patterns of activation in the brain obtained during performance of the individual tasks of vowel identification and story comprehension, to levels of activation when participants performed the two tasks simultaneously during the kana pick-out test. We found that activations of the left dorsal inferior frontal gyrus and superior parietal lobule increase in functional connectivity to a greater extent during the dual task condition compared to the two single task conditions. In contrast, activations of the left fusiform gyrus and middle temporal gyrus, which are significantly involved in picking out letters and complex sentences during story comprehension, respectively, were reduced in the dual task condition compared to during the two single task conditions. These results suggest that increased activations of the dorsal inferior frontal gyrus and superior parietal lobule during dual task performance may be associated with the capacity for attentional resources, and reduced activations of the left fusiform gyrus and middle temporal gyrus may reflect the difficulty of concurrent processing of the two tasks. In addition, the increase in synchronization between the left dorsal inferior frontal gyrus and superior parietal lobule in the dual task condition may induce effective communication between these brain regions and contribute to more attentional processing than in the single task condition, due to greater and more complex demands on voluntary attentional resources.

  Jul. 2012, Neuropsychologia, 50(8) (8), 1998 - 2009, English, International magazine

  Scientific journal


• Synthesis of [(11)C]dehydropravastatin, a PET probe potentially useful for studying OATP1B1 and MRP2 transporters in the liver.

  Ryosuke Ijuin, Tadayuki Takashima, Yasuyoshi Watanabe, Yuichi Sugiyama, Masaaki Suzuki

  Drug transporters mediate the uptake and elimination of drugs in various organs; therefore, having knowledge of how a transporter functions in the body would play a key role in ensuring drug efficacy in in vivo systems. In this context, we designed and synthesized [(11)C]dehydropravastatin, a novel PET probe that would be potentially useful for evaluation of the functions of the OATP1B1 and MRP2 transporters, based on the use of palladium(0)-mediated rapid C-[(11)C]methylation (viz., the rapid cross-coupling between [(11)C]methyl iodide and a boron intermediate).

  Jun. 2012, Bioorganic & medicinal chemistry, 20(12) (12), 3703 - 9, English, International magazine

  Scientific journal


• 慢性疲労症候群における還元型コエンザイムQ10の効果 摂取栄養素との関連を含めて

  福田 早苗, 藤井 比佐子, 中富 康仁, 山口 浩二, 野島 順三, 梶本 修身, 倉恒 弘彦, 渡辺 恭良

  日本疲労学会, Jun. 2012, 日本疲労学会誌, 8(1) (1), 42 - 42, Japanese

  [Refereed]

  Scientific journal


• Effects of daily levels of fatigue and acutely induced fatigue on the visual evoked magnetic response.

  Yoshihito Shigihara, Masaaki Tanaka, Kei Mizuno, Akira Ishii, Emi Yamano, Masami Funakura, Etsuko Kanai, Yasuyoshi Watanabe

  Fatigue is a common complaint in modern society. As photosensitivity is associated with fatigue, this study aimed to clarify the relationship between neural response to visual stimuli and fatigue using a 160-channel whole-head-type magnetoencephalographic system. Twelve healthy male volunteers were enrolled. Participants were randomly assigned to two groups in a single-blinded, crossover fashion to perform acute fatigue-inducing mental task sessions, i.e., 0-back or 2-back test for 30 min. Visual evoked magnetic field (VEF) intensities were evaluated by standardized low-resolution brain electromagnetic tomography modified for a quantifiable method. VEF consisted of two phases, and although acute fatigue did not alter the VEF intensities and the intensities before the acute fatigue-inducing mental task sessions were not correlated with the Chalder's Fatigue Scale scores in either of the two phases, the intensities after the 0-back test trials for 30 min in Phase 1 and those after the 2-back test trials in Phase 2 were significantly correlated with the fatigue scale scores. The daily level of fatigue was related to VEF intensity after the acute mental fatigue loads. Our findings provide new perspectives to evaluate our daily level of fatigue as well as to clarify the neural mechanisms underlying it.

  May 2012, Brain research, 1457, 44 - 50, English, International magazine

  Scientific journal


• Neural substrates activated by viewing others expressing fatigue: a magnetoencephalography study.

  Akira Ishii, Masaaki Tanaka, Emi Yamano, Yasuyoshi Watanabe

  The neural substrates of the fatigue sensation have not been totally identified. Several lines of evidence demonstrate that seeing emotional changes in others activates brain regions involved in experiencing similar emotions. We hypothesized that there exists a mirror system regarding the fatigue sensation and that brain regions associated with the fatigue sensation may be activated by viewing other individuals expressing fatigue. In this study, we attempted to identify the neural substrates activated by viewing other fatigued individuals using magnetoencephalography (MEG). Twelve healthy participants were enrolled in our study after providing written informed consent. During MEG recordings, they viewed a set of pictures projected on a screen. The pictures, which were presented in a randomized order, were of a person with a fatigued or neutral facial expression. When participants viewed pictures of people with fatigued expressions, we were able to estimate equivalent current dipoles (ECDs) in the posterior cingulate cortex (PCC) in 9 of 12 participants approximately 300 ms after the onset of each picture presentation. When they viewed pictures of people with neutral expressions, we were not able to estimate corresponding ECDs for any participant. The PCC is the brain region activated by viewing others expressing fatigue, suggesting existence of the shared neural substrates of felt and observed fatigue.

  May 2012, Brain research, 1455, 68 - 74, English, International magazine

  Scientific journal


• 高速C-[11C]メチル化反応を用いた11C-標識チアミンおよびフルスルチアミンの合成

  土居 久志, 馬渡 彩, 金澤 奨勝, 野崎 聡, 野村 之博, 秋元 浩二, 二宮 伸二, 鈴木 正昭, 渡辺 恭良

  日本分子イメージング学会, May 2012, JSMI Report, 5(2) (2), 85 - 85, Japanese


• Cu-64-DOTA-trastuzumab-PET imaging in patients with HER2-positive breast cancer

  Kenji Tamura, Hiroaki Kurihara, Kan Yonemori, Kazuhiro Takahashi, Yasuhiro Wada, Koki Hasegawa, Fumiaki Koizumi, Hitoshi Tsuda, Makoto Kodaira, Mayu Yunokawa, Chikako Shimizu, Masashi Ando, Yasuyoshi Watanabe, Yasuhiro Fujiwara

  May 2012, JOURNAL OF CLINICAL ONCOLOGY, 30(15) (15), English

  [Refereed]


• PET Imaging Based Evaluation of Hepatobiliary Transport in Humans with (15R)-C-11-TIC-Me

  Tadayuki Takashima, Satoshi Kitamura, Yasuhiro Wada, Masaaki Tanaka, Yoshihito Shigihara, Hideki Ishii, Ryosuke Ijuin, Susumu Shiomi, Takahiro Nakae, Yumiko Watanabe, Yilong Cui, Hisashi Doi, Masaaki Suzuki, Kazuya Maeda, Hiroyuki Kusuhara, Yuichi Sugiyama, Yasuyoshi Watanabe

  May 2012, JOURNAL OF NUCLEAR MEDICINE, 53(5) (5), 741 - 748, English, International magazine

  [Refereed]

  Scientific journal


• Template-assisted and self-activating clicked peptide as a synthetic mimic of the SH2 domain.

  Katsunori Tanaka, Sanae Shirotsuki, Takayuki Iwata, Chika Kageyama, Tsuyoshi Tahara, Satoshi Nozaki, Eric R O Siwu, Satoru Tamura, Shunsuke Douke, Nobutoshi Murakami, Hirotaka Onoe, Yasuyoshi Watanabe, Koichi Fukase

  A new synthetic strategy for obtaining artificial receptors that selectively regulate and/or control specific protein/protein interactions was developed based on the template-assisted and the self-activating click reaction applied to a combinatorial library. Synthetic mimics of the Grb2-SH2 domain, examined as a model case, selectively bound to a target signaling protein to induce cytotoxicity and inhibit tumor growth in vivo.

  Apr. 2012, ACS chemical biology, 7(4) (4), 637 - 45, English, International magazine

  Scientific journal


• 慢性疲労症候群の実生活への影響調査に関する検討

  福田 早苗, 山口 浩二, 中富 康仁, 藤井 比佐子, 野島 順三, 渡辺 恭良, 倉恒 弘彦

  日本疲労学会, Mar. 2012, 日本疲労学会誌, 7(2) (2), 80 - 87, Japanese

  [Refereed]

  Scientific journal


• Effects of pellet stove on recovery from mental fatigue.

  Masaaki Tanaka, Hiromi Yamada, Takayuki Nakamura, Yasuyoshi Watanabe

  BACKGROUND: Exposure to a warm environment has been reported to be effective for recovery from mental fatigue. However, there have been no reports examining the effects of a pellet stove on recovery from mental fatigue. The purpose of this study was to examine the effects of a pellet stove on recovery from mental fatigue. MATERIAL/METHODS: In this placebo-controlled, crossover experiment, 16 healthy volunteers were randomized into the pellet stove and control groups. After a 30-min fatigue-inducing mental task session, participants moved to a recovery room with (pellet stove condition) or without (control condition) a pellet stove to see the image of a pellet stove for 30 min. RESULTS: After the recovery session, the participants exposed to the pellet stove condition showed lower total error counts of a cognitive test, higher levels of subjective healing, comfort, and warmth, and sympathetic nerve activity and higher parasympathetic nerve activity as compared with the control condition. CONCLUSIONS: These results provide evidence that improved cognitive function, subjective mental states, and balance of the autonomic nervous activities result from using a pellet stove during the recovery session. Hence, the pellet stove was effective for the recovery from mental fatigue.

  Mar. 2012, Medical science monitor : international medical journal of experimental and clinical research, 18(3) (3), CR148-53, English, International magazine

  Scientific journal


• Two cases of dementias with motor neuron disease evaluated by Pittsburgh compound B-positron emission tomography.

  Yoshihiro Yamakawa, Hiroyuki Shimada, Suzuka Ataka, Akiko Tamura, Hideki Masaki, Hiroshi Naka, Tsuyoshi Tsutada, Aki Nakanishi, Susumu Shiomi, Yasuyoshi Watanabe, Takami Miki

  We described the cases of two patients with dementia associated with motor neuron disease, the former with frontotemporal dementia (FTD) and the latter with Alzheimer's disease (AD), studied by the Pittsburgh compound B-positron emission tomography (PIB-PET). In the FTD patient, the PIB-PET revealed no amyloid accumulation in the cortex, whilst in the AD patient showed amyloid accumulation mainly in the frontal, parietal and lateral temporal lobes, besides the posterior cingulate gyrus and the precuneus. Thus, PIB-PET might facilitate the discrimination of different proteinopathies that cause neurodegenerative diseases, as dementia associated with ALS.

  Feb. 2012, Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 33(1) (1), 87 - 92, English, International magazine

  Scientific journal


• Effects of monocular deprivation on the spatial pattern of visually induced expression of c-Fos protein.

  K Nakadate, K Imamura, Y Watanabe

  We studied the pattern of expression of a protein product (c-Fos) of immediate-early gene (IEG) in the visual cortex of rats and mice. The basal expression of c-Fos was very low and visual exposure revealed a large number of c-Fos immunopositive cells in the visual cortex. We found that monocular deprivation during the sensitive period of ocular dominance (OD) plasticity significantly changed both the amount and pattern of c-Fos expression upon monocular stimulation of either eye. The number of immunopositive cells in layer IV of binocular subfields of the primary visual cortex (Oc1B) ipsilateral to the stimulated eye was found to be the most sensitive index of the effects of monocular deprivation during the sensitive period, that is, opened eye stimulation induced significantly larger numbers of c-Fos immunopositive cells, whereas closed eye stimulation induced significantly smaller numbers compared with those induced by monocular stimulation in control animals. In the lateral geniculate nucleus and superior colliculus, the pattern of expression of c-Fos following monocular stimulation was not affected by preceding monocular deprivation. Monocular deprivation imposed after the sensitive period did not affect the pattern of induction of c-Fos. Notably, in age-matched old animals that had been raised in total darkness and then experienced monocular deprivation, the distribution and numbers of c-Fos-expressing cells in visual cortex exhibited the same alterations as found in young animals during the sensitive period. These findings suggest that the present activity mapping method using c-Fos as a molecular marker is useful for examining the activity-dependent regulation of cortical plasticity, and provides an alternative method to conventional electrophysiological recording. This method is particularly powerful when applied to knockout or transgenic mice in which sampling biases in electrophysiological recording have been considered inevitable. Furthermore, these findings suggest that c-Fos is involved in OD plasticity as an IEG that transfers neuronal activity to late gene expression.

  Jan. 2012, Neuroscience, 202, 17 - 28, English, International magazine

  [Refereed]

  Scientific journal


• Impaired Selective Attention Caused By Mental Fatigue

  Masaaki Tanaka, Akira Ishii, Yoshihito Shigihara, Seiki Tajima, Masami Funakura, Etsuko Kanai, Yasuyoshi Watanabe

  2012, JOURNAL OF NEUROLOGICAL SCIENCES-TURKISH, 29(3) (3), 542 - 553, English

  [Refereed]

  Scientific journal


• Supraspinal regulation of physical fatigue.

  Masaaki Tanaka, Yasuyoshi Watanabe

  Fatigue, defined as difficulty in initiating or sustaining voluntary activities, can be classified as physical or mental, and physical fatigue can be classified as peripheral or central (spinal or supraspinal). It has been reported that during physical fatigue, sensory input from the peripheral system activates an inhibition system to limit motor output from the primary motor cortex (M1) (supraspinal fatigue) while a motivational input activates a facilitation system to increase motor output from M1 in order to overcome supraspinal fatigue. Hence, the motor output from M1 is primarily determined by the balance between the inhibition and facilitation systems. Here, we review data from behavioral, electrophysiological, and neuroimaging experiments related to supraspinal mechanisms that are thought to regulate motor output from M1 during physical fatigue, and we propose a supraspinal model to regulate physical fatigue as well as a hypothetical model of fatigue in human diseases or syndromes.

  Jan. 2012, Neuroscience and biobehavioral reviews, 36(1) (1), 727 - 34, English, International magazine

  Scientific journal


• Synthesis of [¹¹C]uric acid, using [¹¹C]phosgene, as a possible biomarker in PET imaging for diagnosis of gout.

  Keiji Yashio, Yumiko Katayama, Tadayuki Takashima, Naoki Ishiguro, Hisashi Doi, Masaaki Suzuki, Yasuhiro Wada, Ikumi Tamai, Yasuyoshi Watanabe

  The synthesis and in vivo evaluation of (11)C -labeled uric acid ([(11)C]1), a potential imaging agent for the diagnosis of urate-related life-style diseases, was performed using positron emission tomography (PET) image analysis. First, the synthesis of [(11)C]1 was achieved by reacting 5,6-diaminouracil (2) with (11)C-labeled phosgene ([(11)C]COCl(2)). The radiochemical yield of [(11)C]1 was 37±7% (decay-corrected based on [(11)C]COCl(2)) with specific radioactivities of 96-152GBq/μmol at the end of synthesis (n=6). The average time of radiosynthesis from the end of bombardment, including formulation, was about 30min with >98% radiochemical purity. Second, the synthetic approach to [(11)C]1 was optimized using 5,6-diaminouracil sulfate (3) with [(11)C]COCl(2) in the presence of 1,8-bis(dimethylamino)naphthalene. [(11)C]1 was synthesized in 36±6% radiochemical yield, 89-142GBq/μmol of specific radioactivities, and 98% radiochemical purity by this method (n=5). This allowed the synthesis of [(11)C]1 to be carried out repeatedly and the radiochemical yield, specific radioactivities, average time of synthesis, and radiochemical purity of [(11)C]1 were similar to those obtained using 2. PET studies in rats showed large differences in the accumulation of radioligand in the limbs under normal and hyperuricemic conditions. Thus, an efficient and convenient automated synthesis of [(11)C]1 has been developed, and preliminary PET evaluation of [(11)C]1 confirmed the increased accumulation of radioactivity in the limbs of a rat model of hyperuricemia.

  Jan. 2012, Bioorganic & medicinal chemistry letters, 22(1) (1), 115 - 9, English, International magazine

  Scientific journal


• An alteration in the lateral geniculate nucleus of experimental glaucoma monkeys: in vivo positron emission tomography imaging of glial activation.

  Masamitsu Shimazawa, Yasushi Ito, Yuta Inokuchi, Hajime Yamanaka, Tomohiro Nakanishi, Takuya Hayashi, Bin Ji, Makoto Higuchi, Tetsuya Suhara, Kazuyuki Imamura, Makoto Araie, Yasuyoshi Watanabe, Hirotaka Onoe, Hideaki Hara

  We examined lateral geniculate nucleus (LGN) degeneration as an indicator for possible diagnosis of glaucoma in experimental glaucoma monkeys using positron emission tomography (PET). Chronic intraocular pressure (IOP) elevation was induced by laser trabeculoplasty in the left eyes of 5 cynomolgus monkeys. Glial cell activation was detected by PET imaging with [(11)C]PK11195, a PET ligand for peripheral-type benzodiazepine receptor (PBR), before and at 4 weeks after laser treatment (moderate glaucoma stage). At mild, moderate, and advanced experimental glaucoma stages (classified by histological changes based on the extent of axonal loss), brains were stained with cresyl violet, or antibodies against PBR, Iba-1 (a microglial marker), and GFAP (an activated astrocyte marker). In laser-treated eyes, IOP was persistently elevated throughout all observation periods. PET imaging showed increased [(11)C]PK11195 binding potential in the bilateral LGN at 4 weeks after laser treatment; the increase in the ipsilateral LGN was statistically significant (P<0.05, n = 4). Immunostaining showed bilateral activations of microglia and astrocytes in LGN layers receiving input from the laser-treated eye. PBR-positive cells were observed in LGN layers receiving input from laser-treated eye at all experimental glaucoma stages including the mild glaucoma stage and their localization coincided with Iba-1 positive microglia and GFAP-positive astrocytes. These data suggest that glial activation occurs in the LGN at a mild glaucoma stage, and that the LGN degeneration could be detected by a PET imaging with [(11)C]PK11195 during the moderate experimental glaucoma stage after unilateral ocular hypertension. Therefore, activated glial markers such as PBR in the LGN may be useful in noninvasive molecular imaging for diagnosis of glaucoma.

  2012, PloS one, 7(1) (1), e30526, English, International magazine

  Scientific journal


• Fatigue-associated alterations of cognitive function and electroencephalographic power densities.

  Masaaki Tanaka, Yoshihito Shigihara, Masami Funakura, Etsuko Kanai, Yasuyoshi Watanabe

  Fatigue is a common problem in modern society. We attempted to identify moderate- to long-term fatigue-related alterations in the central nervous system using cognitive tasks and electroencephalography (EEG) measures. The study group consisted of 17 healthy male participants. After saliva samples were collected to measure copy number of human herpesvirus (HHV)-6 DNA to assess the level of moderate- to long-term fatigue, subjects were evaluated using EEG, with their eyes open for 2 min, then closed for 1 min sitting quietly. Thereafter, they completed cognitive task trials to evaluate simple selective attention for 3 min (Task 1) and conflict-controlling selective attention for 6 min (Task 2, which included Stroop trials). The percent error of Task 2 for Stroop trials was positively associated with the copy number of saliva HHV-6 DNA, although the simple selective attention measures in Task 1 did not differ significantly. EEG power densities (especially the alpha power density) during the eye-closed condition were negatively associated with the saliva HHV-6 DNA level. Impaired high-level information processing such as that required for conflict-controlling selective attention in the central nervous system may be a characteristic feature of moderate- to long-term fatigue.

  2012, PloS one, 7(4) (4), e34774, English, International magazine

  Scientific journal


• Clinical features of Pittsburgh compound-B-negative dementia.

  Jun Takeuchi, Hiroyuki Shimada, Suzuka Ataka, Joji Kawabe, Hiroshi Mori, Kei Mizuno, Yasuhiro Wada, Susumu Shiomi, Yasuyoshi Watanabe, Takami Miki

  BACKGROUND/AIMS: We previously found that some cases of clinically diagnosed Alzheimer's disease (AD) were rated as Pittsburgh compound B (PiB) negative by amyloid imaging (i.e. cases of PiB-negative dementia). The present study was designed to analyze the clinical features of PiB-negative dementia patients in detail. METHODS: Of the 64 cases of clinically diagnosed AD, 14 were rated PiB negative. Eleven of these were further analyzed using CSF biomarker levels and findings from MRI, FDG-PET, (123)I-MIBG myocardial scintigraphy and voxel-based morphometry (VBM). RESULTS: When examined by (123)I-MIBG myocardial scintigraphy, the heart/mediastinum ratio was significantly higher in the PiB-negative dementia group than in the dementia with Lewy bodies (DLB) group. Analyses of CSF biomarkers and MRI and FDG-PET findings suggested argyrophilic grain disease (AGD) in 3 cases, frontotemporal lobar degeneration (FTLD) in 3 cases, neurofibrillary tangle-predominant dementia (NFTD) in 1 case, and AD in 2 cases. In the VBM data analysis, the PiB-positive AD group showed significant atrophy of both hippocampi compared with the healthy control group, while the PiB-negative dementia group presented with significant atrophy of the left precuneus. CONCLUSION: PiB-negative dementia is unlikely to include DLB, while it most likely includes diseases of tauopathy, such as FTLD, AGD and NFTD. A better understanding of PiB-negative dementia is expected to further improve the accuracy of the clinical AD diagnosis.

  2012, Dementia and geriatric cognitive disorders, 34(2) (2), 112 - 20, English, International magazine

  Scientific journal


• Reduction of [11C](+)3-MPB binding in brain of chronic fatigue syndrome with serum autoantibody against muscarinic cholinergic receptor.

  Shigeyuki Yamamoto, Yasuomi Ouchi, Daisaku Nakatsuka, Tsuyoshi Tahara, Kei Mizuno, Seiki Tajima, Hirotaka Onoe, Etsuji Yoshikawa, Hideo Tsukada, Masao Iwase, Kouzi Yamaguti, Hirohiko Kuratsune, Yasuyoshi Watanabe

  BACKGROUND: Numerous associations between brain-reactive antibodies and neurological or psychiatric symptoms have been proposed. Serum autoantibody against the muscarinic cholinergic receptor (mAChR) was increased in some patients with chronic fatigue syndrome (CFS) or psychiatric disease. We examined whether serum autoantibody against mAChR affected the central cholinergic system by measuring brain mAChR binding and acetylcholinesterase activity using positron emission tomography (PET) in CFS patients with positive [CFS(+)] and negative [CFS(-)] autoantibodies. METHODOLOGY: Five CFS(+) and six CFS(-) patients, as well as 11 normal control subjects underwent a series of PET measurements with N-[(11)C]methyl-3-piperidyl benzilate [(11)C](+)3-MPB for the mAChR binding and N-[(11)C]methyl-4-piperidyl acetate [(11)C]MP4A for acetylcholinesterase activity. Cognitive function of all subjects was assessed by neuropsychological tests. Although the brain [(11)C](+)3-MPB binding in CFS(-) patients did not differ from normal controls, CFS(+) patients showed significantly lower [(11)C](+)3-MPB binding than CFS(-) patients and normal controls. In contrast, the [(11)C]MP4A index showed no significant differences among these three groups. Neuropsychological measures were similar among groups. CONCLUSION: The present results demonstrate that serum autoantibody against the mAChR can affect the brain mAChR without altering acetylcholinesterase activity and cognitive functions in CFS patients.

  2012, PloS one, 7(12) (12), e51515, English, International magazine

  Scientific journal


• ソマトスタチンアナログを用いた膵内分泌細胞PETイメージング

  佐古 健生, 長谷川 功紀, 西村 三恵, 崔 翼龍, 和田 康弘, 林中 恵美, 片岡 洋祐, 千田 道雄, 渡辺 恭良

  日本分子イメージング学会, Jan. 2012, JSMI Report, 5(1) (1), 20 - 22, Japanese


• PET of Aromatase in Gastric Parietal Cells Using C-11-Vorozole

  Makoto Ozawa, Kayo Takahashi, Ko-hei Akazawa, Tadayuki Takashima, Hiroko Nagata, Hisashi Doi, Takamitsu Hosoya, Yasuhiro Wada, Yilong Cui, Yosky Kataoka, Yasuyoshi Watanabe

  Dec. 2011, JOURNAL OF NUCLEAR MEDICINE, 52(12) (12), 1964 - 1969, English, International magazine

  [Refereed]

  Scientific journal


• 【分子イメージングの最先端】脳内炎症の分子イメージングと片頭痛病態

  崔 翼龍, 渡辺 恭良, 片岡 洋祐

  先端医療技術研究所, Dec. 2011, PET Journal, (16) (16), 14 - 16, Japanese


• Use of [18F]FDOPA-PET for in vivo evaluation of dopaminergic dysfunction in unilaterally 6-OHDA-lesioned rats.

  Kiyoshi Kyono, Tadayuki Takashima, Yumiko Katayama, Toshiyuki Kawasaki, Riyo Zochi, Maki Gouda, Yasuhiro Kuwahara, Kazuhiro Takahashi, Yasuhiro Wada, Hirotaka Onoe, Yasuyoshi Watanabe

  BACKGROUND: We evaluated the utility of L-3,4-dihydroxy-6-[18F]fluoro-phenylalanine ([18F]FDOPA) positron emission tomography (PET) as a method for assessing the severity of dopaminergic dysfunction in unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats by comparing it with quantitative biochemical, immunohistochemical, and behavioral measurements. METHODS: Different doses of 6-OHDA (0, 7, 14, and 28 μg) were unilaterally injected into the right striatum of male Sprague-Dawley rats. Dopaminergic functional activity in the striatum was assessed by [18F]FDOPA-PET, measurement of striatal dopamine (DA) and DA metabolite levels, tyrosine hydroxylase (TH) immunostaining, and methamphetamine-induced rotational testing. RESULTS: Accumulation of [18F]FDOPA in the bilateral striatum was observed in rats pretreated with both aromatic L-amino acid decarboxylase and catechol-O-methyltransferase (COMT) inhibitors. Unilateral intrastriatal injection of 6-OHDA produced a significant site-specific reduction in [18F]FDOPA accumulation. The topological distribution pattern of [18F]FDOPA accumulation in the ipsilateral striatum agreed well with the pattern in TH-stained corresponding sections. A significant positive relationship was found between Patlak plot Ki values and striatal levels of DA and its metabolites (r = 0.958). A significant negative correlation was found between both Ki values (r = -0.639) and levels of DA and its metabolites (r = -0.719) and the number of methamphetamine-induced rotations. CONCLUSIONS: Ki values determined using [18F]FDOPA-PET correlated significantly with the severity of dopaminergic dysfunction. [18F]FDOPA-PET makes it possible to perform longitudinal evaluation of dopaminergic function in 6-OHDA-lesioned rats, which is useful in the development of new drugs and therapies for Parkinson's disease (PD).

  Nov. 2011, EJNMMI research, 1(1) (1), 25 - 25, English, International magazine

  Scientific journal


• Novel System for the Molecular Imaging of Atherosclerotic Plaque with Ga-68-DOTA-ApoA-I Mimetic Peptide (-FAMP)

  Eiji Yahiro, Yoshinari Uehara, Koki Hasegawa, Emi Kawachi, Tsuneo Yano, Yasuyoshi Watanabe, Shin-ichiro Miura, Keijiro Saku

  Nov. 2011, CIRCULATION, 124(21) (21), English

  [Refereed]


• Cognitive dysfunction and mental fatigue in childhood chronic fatigue syndrome--a 6-month follow-up study.

  Junko Kawatani, Kei Mizuno, Seishi Shiraishi, Miyuki Takao, Takako Joudoi, Sanae Fukuda, Yasuyoshi Watanabe, Akemi Tomoda

  OBJECTIVES: Cognitive function was investigated in patients with childhood type chronic fatigue syndrome (CCFS) using the modified advanced trail making test (mATMT). METHODS: mATMT was performed on 19 patients with CCFS and 25 healthy controls of comparable age and sex. The effectiveness of combined treatment with cognitive behavioral therapy (CBT) and pharmacotherapy and its relationship to cognitive function was investigated by evaluation of Chalder's fatigue scale and behavior state before and after treatment for 6 consecutive months. RESULTS: All three tasks (motor skill, selective and alternative attention, and spatial working memory) of the mATMT, especially the difference in reaction time of the alternative attention task, could discriminate CCFS patients from control subjects with 70.5% accuracy (P=0.007). CCFS patients showed significantly lower alternative attention and Chalder's fatigue score before treatment (P=0.037 and 0.002, respectively). A significant improvement in performance status scores was found during the 6 months follow-up period with combined treatment with CBT and medication (P<0.001). Improvement of their cognitive symptoms was significantly correlated with improvement of alternative attention (r=0.653, P=0.002). CONCLUSIONS: Higher-order level cognitive dysfunction affects CCFS pathogenesis. Alternative attention performance evaluated by the mATMT may be used to monitor improvement in patients with CCFS. Combined treatment with CBT and medication may be effective to improve poor attention characteristics associated with CCFS.

  Nov. 2011, Brain & development, 33(10) (10), 832 - 41, English, International magazine

  Scientific journal


• Autonomic nervous alterations associated with daily level of fatigue.

  Masaaki Tanaka, Kei Mizuno, Kouzi Yamaguti, Hirohiko Kuratsune, Akira Fujii, Hiromichi Baba, Kazuya Matsuda, Ayako Nishimae, Toshio Takesaka, Yasuyoshi Watanabe

  BACKGROUND: Fatigue is a common symptom in both sick and healthy people. We examined autonomic nervous alterations associated with fatigue to clarify the mechanisms underlying fatigue. METHODS: The study group consisted of 19 healthy participants who performed a 2-back test for 30 min as a fatigue-inducing mental task session. Before and after the session, they completed the advanced trail making test (ATMT) for 30 min for mental fatigue evaluation, subjective scales to measure fatigue sensation, and underwent electrocardiography to allow assessment of autonomic nerve activities. RESULTS: After the fatigue-inducing task, the total error counts on the ATMT tended to increase (P = 0.076); the ATMT for total trial counts (P = 0.001), the subjective level of fatigue (P < 0.001), and the % low-frequency power (%LF) (P = 0.035) increased significantly; and the % high-frequency power (%HF) decreased compared with before the fatigue-inducing task although this did not reach the statistical significance (P = 0.170). Although LF measured in absolute units did not change significantly before and after the fatigue-inducing task (P = 0.771), and HF measured in absolute units decreased after the task (P = 0.020). The %LF and LF/HF ratio were positively associated with the daily level of fatigue evaluated using Chalder's fatigue scale. In addition, %HF was negatively associated with the fatigue score. CONCLUSIONS: Increased sympathetic activity and decreased parasympathetic activity may be characteristic features of both acute and daily levels of fatigue. Our findings provide new perspectives on the mechanisms underlying fatigue.

  Oct. 2011, Behavioral and brain functions : BBF, 7, 46 - 46, English, International magazine

  Scientific journal


• The involvement of organic anion transporting polypeptide in the hepatic uptake of telmisartan in rats: PET studies with [¹¹C]telmisartan.

  Tadayuki Takashima, Yoshinobu Hashizume, Yumiko Katayama, Machiko Murai, Yasuhiro Wada, Kazuya Maeda, Yuichi Sugiyama, Yasuyoshi Watanabe

  Telmisartan, a selective angiotensin II receptor antagonist, is primarily excreted via hepatobiliary transport. The predominant contribution of organic anion transporting polypeptide (OATP) 1B3 in its hepatic uptake of telmisartan has been demonstrated by in vitro transport studies. In the present study, a quantitative positron emission tomography (PET) methodology was developed for in vivo kinetic assessment of hepatobiliary transport of telmisartan. Serial abdominal PET scans were performed in rats following intravenous administration of [(11)C]telmisartan as a radiotracer. PET scans revealed that [(11)C]telmisartan was localized primarily in the liver and some of the radioactivity moved to the intestine, which corresponds to biliary excretion. Radiometabolite analysis by radiometric HPLC showed that [(11)C]telmisartan was converted to its acylglucuronide, which was mainly detected in bile, but little in plasma and liver. Integration plot analysis revealed that [(11)C]telmisartan was taken up into the liver as rapidly as the hepatic blood flow rate, and the radiometabolite was subsequently excreted into the bile. When rifampicin, a typical Oatp inhibitor, was coadministered with [(11)C]telmisartan in rats, hepatic uptake clearance of [(11)C]telmisartan was significantly decreased, whereas biliary efflux clearance was not changed. Coinjection with unlabeled telmisartan (4 and 10 mg/kg) also decreased hepatic uptake clearance of [(11)C]telmisartan. On the other hand, PET imaging analysis revealed a significant increase of biliary efflux when telmisartan dose was increased to more than 4 mg/kg. These results suggested that the hepatic uptake of [(11)C]telmisartan mainly consists of a saturable process mediated by Oatps in rats, according to noninvasive real-time measurement of tissue radioactivity with the use of PET. The present study with rats is expected to provide the feasibility of PET imaging study to quantitatively estimate OATP1B3 function in humans.

  Oct. 2011, Molecular pharmaceutics, 8(5) (5), 1789 - 98, English, International magazine

  Scientific journal


• Central inhibition regulates motor output during physical fatigue.

  Masaaki Tanaka, Yoshihito Shigihara, Yasuyoshi Watanabe

  Central fatigue refers to a progressive decline in the ability to activate muscles voluntarily. Although the existence of central inhibition of the motor area via visual feedback during physical fatigue was noted in a behavioral study, neural evidence has not been presented. The central mechanism to regulate physical fatigue was examined using a magnetoencephalographic (MEG) system. The study group consisted of eight healthy participants. They were randomly assigned to two groups in a crossover fashion to perform fatigue-inducing physical task sessions, in which they performed repetitive grips of a dominant hand at maximal voluntary contraction levels every second without using Ramachandran's mirror box to see the dominant hand or with using the mirror box to see the mirror reflection of the non-dominant hand to perceive that the fatigued dominant hand was not fatigued. Before and after each session, imagery of maximum grips of the dominant hand was performed for the evaluation with MEG. Beta-band event-related desynchronization (ERD) level of motor readiness magnetic field in the sensorimotor area in the contralateral hemisphere to the handgrips was not altered after the fatigue-inducing session without or with the mirror box. In contrast, the ERD level of motor movement-evoked magnetic field in the contralateral sensorimotor area was reduced after the fatigue-inducing session without the mirror box, although it was not altered after the session with the mirror box. We identified neural evidence of the central inhibition and showed that the visual feedback system is involved in the central mechanism regulating motor output.

  Sep. 2011, Brain research, 1412, 37 - 43, English, International magazine

  Scientific journal


• P-4 Synthesis of a [^<11>C]Capsaicin and In Vivo PET Study of Rat(Poster Presentation)

  Goto Miki, Mizuma Hiroshi, Wada Yasuhiro, Suzuki Masaaki, Onoe Hirotaka, Watanabe Yasuyoshi, Doi Hisashi

  Capsaicin is a pungent and orally ingested compound which is included especially in red pepper. Capsaicin has a variety of important biological activities to human health such as thermal sensing, perspiration, and pain relief etc.. Furthermore, capsaicin is a symbolic compound of vanilloid family which is associated with a receptor of vanilloid receptor subtype 1 (TRPV1). With the aim of demonstrating in vivo molecular imaging of capsaicin by positron emission tomography (PET), we have synthesized a PET molecule probe of 'IC-labeled capsaicin ([^<11>C]capsaicin) by 0-[^<11>C]methylation using [^<11>C]methyl iodide and a corresponding catechol precursor 1. The purified [^<11>C]capsaicin was intravenously injected in rat and the in vivo behaviors of [^<11>C]capsaicin in rat brain and whole body were observed by micro-PET. Interestingly, [^<11>C]capsaicin penetrated the blood-brain barrier and then was accumulated in the brain for approximately 10 min after the administration. In addition, [^<11>C]capsaicin was also accumulated in rat body surface which might be due to the binding of [^<11>C]capsaicin to TRPV1 receptor in the skin. Thus, the obtained PET images were positively correlated with the previously-reported in vitro and in vivo biological activities of capsaicin. Based on the synthesis of [^<11>C]capsaicin, we intend to further synthesize the diverse PET probes of ^<11>C-labeled capsaicin analogs with the objective of not only PET molecule imaging such as biologically important dietary constituents but also drug development focusing on TRPV1.

  Symposium on the chemistry of natural products, Sep. 2011, Symposium on the Chemistry of Natural Products, symposium papers, (53) (53), 493 - 498, Japanese


• Pittsburgh compound B-negative dementia: a possibility of misdiagnosis of patients with non-alzheimer disease-type dementia as having AD.

  Hiroyuki Shimada, Suzuka Ataka, Jun Takeuchi, Hiroshi Mori, Yasuhiro Wada, Yasuyoshi Watanabe, Takami Miki

  Amyloid imaging has been used to detect amyloid deposition in the brain. We performed Pittsburgh compound B (PiB)-positron emission tomography on 63 patients with dementia having cognitive decline or memory disturbance. In addition, we measured the patients' apolipoprotein E4 (apo E4) status and cerebrospinal fluid (CSF) levels of amyloid-β (Aβ)1-42, tau, and P-tau. Finally, the patients were diagnosed as having probable Alzheimer disease (AD) on the basis of their neuropsychological findings and because they met the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association criteria. Among the patients diagnosed with probable AD, 10 patients were PiB negative. The CSF levels of P-tau and tau in PiB-negative patients were significantly lower than those in the PiB-positive patients. In addition, the CSF levels of Aβ1-42 in the PiB-negative patients were significantly higher than those in the PiB-positive patients. None of the PiB-negative patients were apo E4 carriers. These results suggest that the PiB-negative patient group included not only AD patients but also non-AD-type dementia patients. However, our finding is based on a relatively small number of patients and therefore should be replicated in a larger cohort. In addition, it will be necessary to categorize these participants by longitudinal follow-up and postmortem pathological examinations.

  Sep. 2011, Journal of geriatric psychiatry and neurology, 24(3) (3), 123 - 6, English, International magazine

  Scientific journal


• 放射性ソマトスタチンアナログを用いた膵内分泌細胞PETイメージング

  佐古 健生, 長谷川 功紀, 西村 三恵, 崔 翼龍, 和田 康弘, 林中 恵美, 片岡 洋祐, 千田 道雄, 渡辺 恭良

  (一社)日本核医学会, Sep. 2011, 核医学, 48(3) (3), S273 - S273, Japanese


• In vivo expression of cyclooxygenase-1 in activated microglia and macrophages during neuroinflammation visualized by PET with 11C-ketoprofen methyl ester.

  Miho Shukuri, Misato Takashima-Hirano, Keiko Tokuda, Tadayuki Takashima, Kiyoshi Matsumura, Osamu Inoue, Hisashi Doi, Masaaki Suzuki, Yasuyoshi Watanabe, Hirotaka Onoe

  UNLABELLED: Cyclooxygenase (COX)-1 and -2 are prostanoid-synthesizing enzymes that play important roles in the regulation of neuroinflammation and in the development of neurodegenerative disorders. However, the specific functions of these isoforms are still unclear. We recently developed (11)C-labeled ketoprofen methyl ester as a PET probe that targets the COXs for imaging neuroinflammation, though its responsible isoform is yet to be determined. In the present study, we performed ex vivo and in vivo imaging studies with (11)C-ketoprofen methyl ester and determined the contributions of the COX isoforms during the neuroinflammatory process. METHODS: To identify the COX isoform responsible for (11)C-ketoprofen methyl ester in the brain, we examined the ex vivo autoradiography of (11)C-ketoprofen methyl ester using COX-deficient mice. Time-dependent changes in accumulation of (11)C-ketoprofen methyl ester during the neuroinflammatory process were evaluated by PET in rats with hemispheric neuroinflammation induced by intrastriatal injection of lipopolysaccharide or quinolinic acid. In both rat models, cell-type specificity of COX isoform expression during neuroinflammation was identified immunohistochemically. RESULTS: Ex vivo autoradiographic analysis of COX-deficient mice revealed a significant reduction of (11)C-ketoprofen methyl ester accumulation only in COX-1-deficient mice, not COX-2-deficient mice. PET of rats after intrastriatal injection of lipopolysaccharide showed a significant increase in accumulation of (11)C-ketoprofen methyl ester in the inflamed area. This increase was evident at the early phase of 6 h, peaked at day 1, and then returned to basal levels by day 7. In addition, immunohistochemical analysis revealed that the population of activated microglia and macrophages was elevated at the early phase with COX-1 expression but not COX-2. A significant increase in (11)C-ketoprofen methyl ester accumulation was also observed at day 1 after intrastriatal injection of quinolinic acid, with increased COX-1-expressing activated microglia and macrophages. CONCLUSION: We have identified (11)C-ketoprofen methyl ester as a COX-1-selective PET probe, and using this, we have also demonstrated a time-dependent expression of COX-1 in activated microglia and macrophages during the neuroinflammatory process in the living brain. Thus, COX-1 may play a crucial role in the pathology of neuroinflammation and might be a critical target for the diagnosis and therapy of neurodegenerative disorders.

  Jul. 2011, Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 52(7) (7), 1094 - 101, English, International magazine

  Scientific journal


• Low visual information-processing speed and attention are predictors of fatigue in elementary and junior high school students.

  Kei Mizuno, Masaaki Tanaka, Sanae Fukuda, Emi Yamano, Yoshihito Shigihara, Kyoko Imai-Matsumura, Yasuyoshi Watanabe

  BACKGROUND: Fatigue is a common complaint among elementary and junior high school students, and is known to be associated with reduced academic performance. Recently, we demonstrated that fatigue was correlated with decreased cognitive function in these students. However, no studies have identified cognitive predictors of fatigue. Therefore, we attempted to determine independent cognitive predictors of fatigue in these students. METHODS: We performed a prospective cohort study. One hundred and forty-two elementary and junior high school students without fatigue participated. They completed a variety of paper-and-pencil tests, including list learning and list recall tests, kana pick-out test, semantic fluency test, figure copying test, digit span forward test, and symbol digit modalities test. The participants also completed computerized cognitive tests (tasks A to E on the modified advanced trail making test). These cognitive tests were used to evaluate motor- and information-processing speed, immediate and delayed memory function, auditory and visual attention, divided and switching attention, retrieval of learned material, and spatial construction. One year after the tests, a questionnaire about fatigue (Japanese version of the Chalder Fatigue Scale) was administered to all the participants. RESULTS: After the follow-up period, we confirmed 40 cases of fatigue among 118 students. In multivariate logistic regression analyses adjusted for grades and gender, poorer performance on visual information-processing speed and attention tasks was associated with increased risk of fatigue. CONCLUSIONS: Reduced visual information-processing speed and poor attention are independent predictors of fatigue in elementary and junior high school students.

  Jun. 2011, Behavioral and brain functions : BBF, 7, 20 - 20, English, International magazine

  Scientific journal


• Neural compensation mechanisms to regulate motor output during physical fatigue.

  Masaaki Tanaka, Yasuyoshi Watanabe

  Central fatigue refers to a progressive decline in the ability to activate muscles voluntarily. Although the neural mechanisms of central inhibition of the motor area during physical fatigue have been widely investigated, mechanisms supporting motor output during fatigue remain to be clarified. In this study, the compensation mechanisms to regulate physical fatigue were examined using a 160-channel whole-head-type magnetoencephalographic (MEG) system. The study group consisted of nine right-handed healthy participants. After enrollment, participants performed a fatigue-inducing physical task session in which they performed repetitive grips of the right hand at maximal voluntary contraction levels every second. Before and after the session, imagery of maximum grips of the right hand was performed for evaluation with MEG. Although beta-band event-related desynchronization (ERD) level of the motor movement-evoked magnetic field in the left sensorimotor area showed a trend toward reduction after the fatigue session, the ERD level of the motor movement-evoked magnetic field in the right sensorimotor area was increased after the session. The ERD level in the prefrontal area was increased after the fatigue-inducing session. The ERD level in the left sensorimotor area was positively associated with that in the right sensorimotor area after the fatigue-inducing task session. In addition, ERD levels in the left and right sensorimotor areas had trends toward positive correlations with that in the prefrontal area. These results suggest that the ipsilateral sensorimotor and prefrontal areas are brain regions associated with compensation mechanisms to support motor output under the condition of physical fatigue.

  Jun. 2011, Brain research, 1395, 46 - 52, English, International magazine

  Scientific journal


• Relationship between cognitive functions and prevalence of fatigue in elementary and junior high school students.

  Kei Mizuno, Masaaki Tanaka, Sanae Fukuda, Kyoko Imai-Matsumura, Yasuyoshi Watanabe

  BACKGROUND: Fatigue is a common complaint among elementary and junior high school students, and is related to poor academic performance. Since grade-dependent development of cognitive functions also influences academic performance, we attempted to determine whether cognitive functions were associated with the prevalence of fatigue. METHODS: Participants were 148 elementary school students from 4th- to 6th-grades and 152 junior high school students from 7th- to 9th-grades. Participants completed a questionnaire about fatigue (Japanese version of the Chalder Fatigue Scale) and paper-and-pencil and computerized cognitive tests which could evaluate the abilities of motor processing, immediate, delayed and working memory, selective, divided and alternative attention, retrieve learned material, and spatial construction. RESULTS: We found that in multivariate logistic regression analyses adjusted for grade and gender, slow motor processing was positively correlated with the prevalence of fatigue in the elementary school students and decreases in working memory and divided and alternative attention processing were positively correlated with the prevalence of fatigue in the junior high school students. CONCLUSION: The grade-dependent development of cognitive function influences the severity of fatigue in elementary and junior high school students.

  Jun. 2011, Brain & development, 33(6) (6), 470 - 9, English, International magazine

  Scientific journal


• First automatic radiosynthesis of 11C labeled Telmisartan using a multipurpose synthesizer for clinical research use.

  Hitoshi Iimori, Yoshinobu Hashizume, Masahiro Sasaki, Yoshinobu Kajiwara, Yuichi Sugimoto, Yuichi Sugiyama, Yasuyoshi Watanabe, Michio Senda

  OBJECTIVE: Telmisartan, a nonpeptide angiotensin II AT1 receptor antagonist, is an antihypertensive drug. Positron emission tomography (PET) imaging with [(11)C]Telmisartan is expected to provide information about the whole body pharmacokinetics of telmisartan as well as the transport function of hepatic OATP1B3. We developed a first automatic preparation system of [(11)C]Telmisartan to applicable clinical research using a new (11)C and (18)F multipurpose synthesizer. METHODS: Two milligrams of precursor (1) in 5 μl of 1 M KOH in 0.5 ml of dimethyl sulfoxide was reacted with [(11)C]CH(3)I for 5 min at 120°C. The resultant solution was hydrolyzed with 1 M NaOH at 100°C for 3 min. The neutralization was carried out with acetic acid, followed by purification with high-performance liquid chromatography. The desired radioactive fraction was collected and solvent was replaced by 10 ml saline containing 0.3 ml of EtOH and 0.5 ml of PEG400, and then passed through a sterile 0.22 μm filter (Millex-GV, Millipore) to a pyrogen-free vial as the final product. RESULTS: The yield of [(11)C]Telmisartan for clinical research use was 16.8 ± 2.9% EOB as decay corrected (n = 8, mean ± SD) in 32-36 min. The radiochemical purity of [(11)C]Telmisartan was >97%, and specific activity was higher than 86.3 MBq/nmol. CONCLUSIONS: We succeeded in the first synthesis of [(11)C]Telmisartan for clinical research use by appropriate quality tests.

  Jun. 2011, Annals of nuclear medicine, 25(5) (5), 333 - 7, English, Domestic magazine

  Scientific journal


• Developmental Changes in P-Glycoprotein Function in the Blood-Brain Barrier of Nonhuman Primates: PET Study with R-C-11-Verapamil and C-11-Oseltamivir

  Tadayuki Takashima, Chihiro Yokoyama, Hiroshi Mizuma, Hajime Yamanaka, Yasuhiro Wada, Kayo Onoe, Hiroko Nagata, Shusaku Tazawa, Hisashi Doi, Kazuhiro Takahashi, Masataka Morita, Motomu Kanai, Masakatsu Shibasaki, Hiroyuki Kusuhara, Yuichi Sugiyama, Hirotaka Onoe, Yasuyoshi Watanabe

  Jun. 2011, JOURNAL OF NUCLEAR MEDICINE, 52(6) (6), 950 - 957, English, International magazine

  [Refereed]

  Scientific journal


• Mental fatigue caused by prolonged cognitive load associated with sympathetic hyperactivity.

  Kei Mizuno, Masaaki Tanaka, Kouzi Yamaguti, Osami Kajimoto, Hirohiko Kuratsune, Yasuyoshi Watanabe

  BACKGROUND: It is known that chronic fatigue is associated with sympathetic hyperactivity. However, the relationship between autonomic function and mental fatigue caused by a prolonged mental load in healthy humans is still unclear. Thus, in order to clarify the mechanisms underlying mental fatigue, we examined the association between mental fatigue and autonomic functions. METHODS: The study group comprised 10 healthy participants. To induce mental fatigue, participants performed mental tasks, which consisted of the advanced trail making test, kana pick-out test and mirror drawing test, for 8 hr, corresponding to a normal work day. Autonomic functions were measured by accelerated plethysmography before and after the fatigue-inducing mental tasks. As a control, the same participants completed an 8-hr relaxation session 4 weeks before the fatigue session. RESULTS: After the 8-hr relaxation session, low-frequency component power (LF), high-frequency component power (HF) and low-frequency component power/high-frequency component power ratio (LF/HF ratio) were not changed from baseline. In contrast, after the fatigue session, the HF and LF/HF ratio were significantly changed from baseline; specifically, the HF was lower and LF/HF ratio was higher as compared to those after the relaxation session. CONCLUSIONS: Sympathetic hyperactivity based on decreased parasympathetic activity is associated with mental fatigue induced by prolonged cognitive load.

  May 2011, Behavioral and brain functions : BBF, 7, 17 - 17, English, International magazine

  Scientific journal


• Increase in hypothalamic aromatase in macaque monkeys treated with anabolic-androgenic steroids: PET study with [11C]vorozole.

  Kayo Takahashi, Kayo Onoe, Hisashi Doi, Hiroko Nagata, Gen Yamagishi, Takamitsu Hosoya, Yasuhisa Tamura, Yasuhiro Wada, Hajime Yamanaka, Chihiro Yokoyama, Hiroshi Mizuma, Tadayuki Takashima, Mats Bergström, Hirotaka Onoe, Bengt Långström, Yasuyoshi Watanabe

  May 2011, Neuroreport, 22(7) (7), 326 - 30, English, International magazine

  [Refereed]

  Scientific journal


• 新しい分子標的と分子プローブ創製 新規aromataseイメージングPETプローブ

  高橋 佳代, 細谷 孝充, 尾上 嘉代, 長田 浩子, 土居 久志, 和田 康弘, 高島 忠之, 田村 泰久, 渡辺 由美子, 田中 雅彰, 石井 聡, 鈴木 正昭, 尾上 浩隆, 渡辺 恭良

  日本分子イメージング学会, May 2011, JSMI Report, 4(2) (2), 30 - 30, Japanese


• Progress in axonal and neuronal degenerations of visual pathways in experimental glaucoma monkeys: Imaging studies with PET and DTI

  Hirotaka Onoe, Takuya Hayashi, Masamitsu Shimazawa, Yuta Inokuchi, Yasushi Ito, Hajime Yamanaka, Yasuyoshi Watanabe, Hideaki Hara

  May 2011, JOURNAL OF NUCLEAR MEDICINE, 52, English


• Changes in cognitive functions of students in the transitional period from elementary school to junior high school.

  Kei Mizuno, Masaaki Tanaka, Sanae Fukuda, Tetsuya Sasabe, Kyoko Imai-Matsumura, Yasuyoshi Watanabe

  BACKGROUND: When students proceed to junior high school from elementary school, rapid changes in the environment occur, which may cause various behavioral and emotional problems. However, the changes in cognitive functions during this transitional period have rarely been studied. METHODS: In 158 elementary school students from 4th- to 6th-grades and 159 junior high school students from 7th- to 9th-grades, we assessed various cognitive functions, including motor processing, spatial construction ability, semantic fluency, immediate memory, delayed memory, spatial and non-spatial working memory, and selective, alternative, and divided attention. RESULTS: Our findings showed that performance on spatial and non-spatial working memory, alternative attention, divided attention, and semantic fluency tasks improved from elementary to junior high school. In particular, performance on alternative and divided attention tasks improved during the transitional period from elementary to junior high school. CONCLUSION: Our finding suggests that development of alternative and divided attention is of crucial importance in the transitional period from elementary to junior high school.

  May 2011, Brain & development, 33(5) (5), 412 - 20, English, International magazine

  Scientific journal


• Efficient sequential synthesis of PET Probes of the COX-2 inhibitor [11C]celecoxib and its major metabolite [11C]SC-62807 and in vivo PET evaluation.

  Misato Takashima-Hirano, Tadayuki Takashima, Yumiko Katayama, Yasuhiro Wada, Yuichi Sugiyama, Yasuyoshi Watanabe, Hisashi Doi, Masaaki Suzuki

  Synthesis of [(11)C]celecoxib, a selective COX-2 inhibitor, and [(11)C]SC-62807, a major metabolite of celecoxib, were achieved and the potential of these PET probes for assessing the function of drug transporter in biliary excretion was evaluated. The synthesis of [(11)C]celecoxib was achieved in one-pot by reacting [(11)C]methyl iodide with an excess of the corresponding pinacol borate precursor using Pd(2)(dba)(3), P(o-tolyl)(3), and K(2)CO(3) (1:4:9) in DMF. The radiochemical yield of [(11)C]celecoxib was 63±23% (decay-corrected, based on [(11)C]CH(3)I) (n=7) with a specific radioactivity of 83±23GBq/μmol (n=7). The average time of synthesis from end of bombardment including formulation was 30min with >99% radiochemical purity. [(11)C]SC-62807 was synthesized from [(11)C]celecoxib by further rapid oxidation in the presence of excess KMnO(4) with microwave irradiation. The radiochemical yield of [(11)C]SC-62807 was 55±9% (n=3) (decay-corrected, based on [(11)C]celecoxib) with a specific radioactivity of 39±4GBq/μmol (n=3). The average time of synthesis from [(11)C]celecoxib including formulation was 20min and the radiochemical purity was >99%. PET studies in rats and the metabolite analyzes of [(11)C]celecoxib and [(11)C]SC-62807 showed largely different excretion processes, and consequently, [(11)C]SC-62807 was rapidly excreted via hepatobiliary excretion without further metabolism. [(11)C]SC-62807 was shown to have a high potential as a PET probe for evaluating drug transporter function in biliary excretion.

  May 2011, Bioorganic & medicinal chemistry, 19(9) (9), 2997 - 3004, English, International magazine

  [Refereed]

  Scientific journal


• 早期緑内障サルの外側膝状体内ミクログリアの活性化

  嶋澤 雅光, 井口 勇太, 伊藤 保志, 山中 創, 林 拓也, 季 斌, 樋口 真人, 須原 哲也, 今村 一之, 新家 眞, 渡辺 恭良, 尾上 浩隆, 原 英彰

  日本分子イメージング学会, May 2011, JSMI Report, 4(2) (2), 130 - 130, Japanese

  [Refereed]


• 拡散テンソル画像でみた神経変性動態 緑内障視神経障害モデル動物における観察

  林 拓也, 原 英彰, 嶋澤 雅光, 井口 勇太, 伊藤 保志, 合瀬 恭幸, 渡部 浩司, 飯田 英博, 山中 創, 渡辺 恭良, 尾上 浩隆

  日本分子イメージング学会, May 2011, JSMI Report, 4(2) (2), 92 - 92, Japanese

  [Refereed]


• PETを用いた核酸医薬DDSの動態評価 クリック化学法による18F-標識化オリゴヌクレオチドの有用性の実証

  向井 英史, 尾崎 大起, 長田 浩子, 崔 翼龍, 窪山 剛之, 和田 康弘, 今西 武, 兒玉 哲也, 小比賀 聡, 鈴木 正昭, 土居 久志, 渡辺 恭良

  日本DDS学会, May 2011, Drug Delivery System, 26(3) (3), 294 - 294, Japanese


• 脳内炎症の分子イメージングと片頭痛病態

  崔 翼龍, 高島 忠之, 高島 好聖, 佐古 健生, 奥山 香里, 林中 恵美, 和田 康弘, 土居 久志, 渡辺 恭良, 片岡 洋祐

  日本分子イメージング学会, May 2011, JSMI Report, 4(2) (2), 47 - 47, Japanese


• ソマトスタチンアナログを用いた膵内分泌細胞PETイメージング

  佐古 健生, 長谷川 功紀, 西村 三恵, 崔 翼龍, 和田 康弘, 林中 恵美, 片岡 洋祐, 千田 道雄, 渡辺 恭良

  日本分子イメージング学会, May 2011, JSMI Report, 4(2) (2), 98 - 98, Japanese


• 脳内炎症の分子イメージングと片頭痛病態

  崔 翼龍, 高島 忠之, 高島 好聖, 佐古 健生, 奥山 香里, 林中 恵美, 和田 康弘, 土居 久志, 渡辺 恭良, 片岡 洋祐

  日本分子イメージング学会, May 2011, JSMI Report, 4(2) (2), 126 - 126, Japanese


• 理研CMISにおける64Cu-DOTA-Trastuzumab注射液の治験薬GMP製造への取り組み

  田沢 周作, 長谷川 功紀, 高橋 和弘, 矢野 恒夫, 渡辺 恭良

  (株)じほう, Mar. 2011, PHARM TECH JAPAN, 27(3) (3), 431 - 440, Japanese


• Involvement of endoplasmic reticulum stress on neuronal cell death in the lateral geniculate nucleus in the monkey glaucoma model.

  Yasushi Ito, Masamitsu Shimazawa, Yuta Inokuchi, Hajime Yamanaka, Kazuhiro Tsuruma, Kazuyuki Imamura, Hirotaka Onoe, Yasuyoshi Watanabe, Makoto Aihara, Makoto Araie, Hideaki Hara

  We investigated whether endoplasmic reticulum (ER) stress was involved in the pathophysiological mechanisms underlying neuronal death of the lateral geniculate nucleus (LGN) after intraocular pressure (IOP) elevation. Five cynomolgus monkeys, four with a glaucomatous left eye after laser photocoagulation treatment and one normal monkey, were studied. At 4, 11, 15 and 24 weeks after the laser photocoagulation treatment, the numbers of LGN neurons and atrophy were immunohistochemically evaluated using anti-parvalbumin-antibody, which was used to specifically label relay neurons connecting to the visual cortex. In addition, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cells, polyubiquitin, and production of ER stress-related proteins, such as the phosphorylation of eukaryotic initiation factor 2α (p-eIF2α) and C/EBP-homologous protein (CHOP), were also measured using in situ hybridization and immunostaining. Loss of neurons and/or neuronal atrophy in layers 1, 4 and 6 of the LGN on the contralateral side were observed at 4-24 weeks after the laser photocoagulation treatment. Furthermore, the retinal input from the high IOP eye projected to layers 2 (magnocellular layer), 3 and 5 (parvocellular layer) on the ipsilateral side. Neuronal damage was also confirmed in these layers. In the LGN region, TUNEL-positive cells, polyubiquitin, p-eIF2α and CHOP were also detected at 11-24 weeks after the laser photocoagulation treatment. These findings indicate that ER stress may play a pivotal role in neuronal death of the LGN after IOP elevation.

  Mar. 2011, The European journal of neuroscience, 33(5) (5), 843 - 55, English, International magazine

  Scientific journal


• Positron Emission Tomography(PET)を用いた薬物の体内動態評価 薬物の消化管吸収過程の解析

  片岡 誠, 高島 忠之, 新垣 友隆, 政岡 祥江, 佐久間 信至, 片山 由美子, 林中 恵美, 崔 翼龍, 和田 康弘, 渡辺 恭良, 山下 伸二

  (公社)日本薬学会, Mar. 2011, 日本薬学会年会要旨集, 131年会(4) (4), 200 - 200, Japanese


• Practical synthesis of precursor of [N-methyl-11C]vorozole, an efficient PET tracer targeting aromatase in the brain.

  Kayo Takahashi, Gen Yamagishi, Toshiyuki Hiramatsu, Ayako Hosoya, Kayo Onoe, Hisashi Doi, Hiroko Nagata, Yasuhiro Wada, Hirotaka Onoe, Yasuyoshi Watanabe, Takamitsu Hosoya

  A practical method to prepare precursor of [N-methyl-(11)C]vorozole ([(11)C]vorozole), an efficient positron emission tomography (PET) tracer for imaging aromatase in the living body, was established. Sufficient amount of the racemate including norvorozole, a demethylated vorozole derivative used as a precursor of [(11)C]vorozole, became available by means of high-yield eight-step synthesis. The enantiomers were separated by preparative HPLC using a chiral stationary phase column to give optically pure norvorozole and its enantiomer. From the latter, ent-[(11)C]vorozole, an enantiomer of [(11)C]vorozole, was prepared and used in the PET study for the first time, which was shown to bind very weakly to aromatase in rhesus monkey brain supporting the previous pharmacological results. The stable supply of norvorozole will facilitate further researches on aromatase in the living body including brain by the PET technique.

  Feb. 2011, Bioorganic & medicinal chemistry, 19(4) (4), 1464 - 70, English, International magazine

  Scientific journal


• PET Imaging of the Gastrointestinal Absorption of Orally Administered Drugs in Conscious and Anesthetized Rats

  Shinji Yamashita, Tadayuki Takashima, Makoto Kataoka, Hiroyuki Oh, Shinji Sakuma, Masayuki Takahashi, Norio Suzuki, Emi Hayashinaka, Yasuhiro Wada, Yilong Cui, Yasuyoshi Watanabe

  Feb. 2011, JOURNAL OF NUCLEAR MEDICINE, 52(2) (2), 249 - 256, English, International magazine

  [Refereed]

  Scientific journal


• Relationship between cognitive function and prevalence of decrease in intrinsic academic motivation in adolescents.

  Kei Mizuno, Masaaki Tanaka, Sanae Fukuda, Kyoko Imai-Matsumura, Yasuyoshi Watanabe

  BACKGROUND: Decrease in intrinsic motivation is a common complaint among elementary and junior high school students, and is related to poor academic performance. Since grade-dependent development of cognitive functions also influences academic performance by these students, we examined whether cognitive functions are related to the prevalence of decrease in intrinsic academic motivation. METHODS: The study group consisted of 134 elementary school students from 4th to 6th grades and 133 junior high school students from 7th to 9th grades. Participants completed a questionnaire on intrinsic academic motivation. They also performed paper-and-pencil and computerized cognitive tests to measure abilities in motor processing, spatial construction, semantic fluency, immediate memory, short-term memory, delayed memory, spatial working memory, and selective, alternative, and divided attention. RESULTS: In multivariate logistic regression analyses adjusted for grade and gender, scores of none of the cognitive tests were correlated with the prevalence of decrease in intrinsic academic motivation in elementary school students. However, low digit span forward test score and score for comprehension of the story in the kana pick-out test were positively correlated with the prevalence of decrease in intrinsic academic motivation in junior high school students. CONCLUSIONS: The present findings suggest that decrease in capacity for verbal memory is associated with the prevalence of decrease in intrinsic academic motivation among junior high school students.

  Jan. 2011, Behavioral and brain functions : BBF, 7, 4 - 4, English, International magazine

  Scientific journal


• The neural correlates of the mirror system of fatigue: A magnetoencephalography study

  Akira Ishii, Masaaki Tanaka, Emi Yamano, Yasuyoshi Watanabe

  2011, NEUROSCIENCE RESEARCH, 71, E268 - E268, English

  [Refereed]


• Microglial activation in patients with chronic fatigue syndrome: A positron emission tomography study with [C-11]PK11195

  Yasuhito Nakatomi, Kei Mizuno, Akira Ishii, Yasuhiro Wada, Masaaki Tanaka, Shusaku Tazawa, Kayo Onoe, Sanae Fukuda, Joji Kawabe, Kazuhiro Takahashi, Yosky Kataoka, Susumu Shiomi, Kouzi Yamaguti, Masaaki Inaba, Hirohiko Kuratsune, Yasuyoshi Watanabe

  2011, NEUROSCIENCE RESEARCH, 71, E199 - E199, English

  [Refereed]


• Current Practice of producing Cu-64-DOTA-Trastuzumab Injections in RIKEN CMIS according to GMP for Investigational Products

  Shusaku Tazawa, Koki Hasegawa, Yousuke Kanayama, Riyo Zochi, Yoko Morimoto, Kazutaka Hayashi, Akiko Tachibana, Kazuhiro Takahashi, Tsuneo Yano, Yasuyoshi Watanabe

  2011, JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS, 54, S160 - S160, English

  [Refereed]


• Stoichiometry-focused (18)F-labeling of alkyne-substituted oligodeoxynucleotides using azido([(18)F]fluoromethyl)benzenes by Cu-catalyzed Huisgen reaction.

  Takeshi Kuboyama, Motoi Nakahara, Masafumi Yoshino, Yilong Cui, Takeo Sako, Yasuhiro Wada, Takeshi Imanishi, Satoshi Obika, Yasuyoshi Watanabe, Masaaki Suzuki, Hisashi Doi

  A novel method for (18)F-radiolabeling of oligodeoxynucleotides (ODNs) by a Cu-catalyzed Huisgen reaction has been developed by using the lowest possible amount of the precursor biomolecule for the realization of stoichiometry-oriented PET (positron emission tomography) chemistry. Under the optimized cyclization conditions of p- or m-azido([(18)F]fluoromethyl)benzene and alkyne-substituted ODN (20nmol) at 40°C for 15min in the presence of CuSO(4), TBTA [tris((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)amine], and sodium ascorbate (2:1:2), the synthesis of (18)F-labeled ODNs with sufficiently high radioactivities of 2.1-2.5GBq and specific radioactivities of 1800-2400GBq/μmol have been accomplished for use in animal and human PET studies.

  Jan. 2011, Bioorganic & medicinal chemistry, 19(1) (1), 249 - 55, English, International magazine

  Scientific journal


• Gustatory imagery reveals functional connectivity from the prefrontal to insular cortices traced with magnetoencephalography.

  Masayuki Kobayashi, Tetsuya Sasabe, Yoshihito Shigihara, Masaaki Tanaka, Yasuyoshi Watanabe

  Our experience and prejudice concerning food play an important role in modulating gustatory information processing; gustatory memory stored in the central nervous system influences gustatory information arising from the peripheral nervous system. We have elucidated the mechanism of the "top-down" modulation of taste perception in humans using functional magnetic resonance imaging (fMRI) and demonstrated that gustatory imagery is mediated by the prefrontal (PFC) and insular cortices (IC). However, the temporal order of activation of these brain regions during gustatory imagery is still an open issue. To explore the source of "top-down" signals during gustatory imagery tasks, we analyzed the temporal activation patterns of activated regions in the cerebral cortex using another non-invasive brain imaging technique, magnetoencephalography (MEG). Gustatory imagery tasks were presented by words (Letter G-V) or pictures (Picture G-V) of foods/beverages, and participants were requested to recall their taste. In the Letter G-V session, 7/9 (77.8%) participants showed activation in the IC with a latency of 401.7±34.7 ms (n = 7) from the onset of word exhibition. In 5/7 (71.4%) participants who exhibited IC activation, the PFC was activated prior to the IC at a latency of 315.2±56.5 ms (n = 5), which was significantly shorter than the latency to the IC activation. In the Picture G-V session, the IC was activated in 6/9 (66.7%) participants, and only 1/9 (11.1%) participants showed activation in the PFC. There was no significant dominance between the right and left IC or PFC during gustatory imagery. These results support those from our previous fMRI study in that the Letter G-V session rather than the Picture G-V session effectively activates the PFC and IC and strengthen the hypothesis that the PFC mediates "top-down" control of retrieving gustatory information from the storage of long-term memories and in turn activates the IC.

  2011, PloS one, 6(7) (7), e21736, English, International magazine

  Scientific journal


• Positron Emission Tomography (PET) study for the evaluation of in vivo hepatobiliary transport using [11C] telmisartan

  Tadayuki Takashima, Yoshinobu Hashizume, Hisashi Doi, Yasuhiro Wada, Yasuyoshi Watanabe, Michio Senda, Tomohiko Yamane, Masahiro Sasaki, Keiji Shimizu, Akemi Iwamoto, Hiromitsu Kageyama, Kazuya Maeda, Hiroyuki Kusuhara, Yuichi Sugiyama

  Dec. 2010, Japanese Pharmacology and Therapeutics, 38(2) (2), S103 - S109, Japanese

  International conference proceedings


• Cortical activation during color discrimination task in macaques as revealed by positron emission tomography.

  Narumi Katsuyama, Kazuyuki Imamura, Hirotaka Onoe, Hide-Ki Tanaka, Kayo Onoe, Hideo Tsukada, Yasuyoshi Watanabe

  Physiological and lesion studies have shown that the anterior inferior temporal (IT) cortex (aITC) is involved in the color vision of macaque monkeys. However, some functional imaging studies using awake monkeys contradicted the involvement of aITC in color vision. Thus, in most of the imaging studies, cortical activation has been observed during a fixation task. However, because the neuronal activity of aITC is highly affected by the behavioral task, it is desirable to investigate cortical activity during a color discrimination task to determine the functional role of aITC in the color vision of macaque monkeys. In this study, we investigated the cortical activity of aITC of macaque monkeys during color discrimination by positron emission tomography. Two monkeys were trained in a color discrimination task. Cortical areas involved in color processing were investigated by comparing activities during the color discrimination and lever release tasks. In addition to area V4 and the posterior IT cortex (pITC), we found color-related activities in the anterior IT gyrus. Consistent activation was observed in the region posterior to the anterior medial temporal sulcus (AMTS), although the exact location and the size of activations differed between monkeys and hemispheres. We also found color-related activities in the anterior portion of the superior temporal sulcus (STS), suggesting its involvement in the color vision. The present results revealed that aITC is involved in the color vision of macaque monkeys by a functional imaging technique.

  Nov. 2010, Neuroscience letters, 484(3) (3), 168 - 73, English, International magazine

  Scientific journal


• Positron Emission Tomography Studies Using (15R)-16-m-[C-11]tolyl-17,18,19,20-tetranorisocarbacyclin Methyl Ester for the Evaluation of Hepatobiliary Transport

  Tadayuki Takashima, Hiroko Nagata, Takahiro Nakae, Yilong Cui, Yasuhiro Wada, Satoshi Kitamura, Hisashi Doi, Masaaki Suzuki, Kazuya Maeda, Hiroyuki Kusuhara, Yuichi Sugiyama, Yasuyoshi Watanabe

  Nov. 2010, JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 335(2) (2), 314 - 323, English, International magazine

  [Refereed]

  Scientific journal


• Noninvasive imaging of dendrimer-type N-glycan clusters: in vivo dynamics dependence on oligosaccharide structure.

  Katsunori Tanaka, Eric R O Siwu, Kaori Minami, Koki Hasegawa, Satoshi Nozaki, Yousuke Kanayama, Koichi Koyama, Weihsu C Chen, James C Paulson, Yasuyoshi Watanabe, Koichi Fukase

  Oct. 2010, Angewandte Chemie (International ed. in English), 49(44) (44), 8195 - 200, English, International magazine

  Scientific journal


• [Microdose clinical trial--impact of PET molecular imaging].

  Tsuneo Yano, Yasuyoshi Watanabe

  Microdose (MD) clinical trial and exploratory IND study including sub-therapeutic dose and therapeutic dose which are higher than microdoses are expected to bring about innovations in drug development. The outlines of guidances for microdose clinical trial and ICH-M3 (R2) issued by the MHLW in June, 2008, and February, 2010, are first explained, respectively, and some examples of their application to clinical developments of therapeutic drugs in the infection and cancer fields are introduced. Especially, thanks to the progress of molecular imaging research, a new field of drug development is explored by using imaging biomarkers for efficacy or safety evaluation which visualize biomarkers by PET imaging agents. Finally, the roadmap for drug development in infection and cancer fields utilizing PET molecular imaging is discussed.

  Oct. 2010, Gan to kagaku ryoho. Cancer & chemotherapy, 37(10) (10), 1839 - 48, Japanese, Domestic magazine

  Scientific journal


• Azaelectrocyclization-Based Labeling of Proteins and Cell Surfaces: Application to Noninvasive Imaging of N-Glycans

  Tanaka Katsunori, Minami Kaori, Siwu Eric R. O., Masuyama Tatsuro, Koyama Koichi, Yokoi Satomi, Hasegawa Koki, Tahara Tsuyoshi, Mizuma Hiroshi, Nozaki Satoshi, Kanayama Yousuke, Wada Yasuhiro, Onoe Hirotaka, Watanabe Yasuyoshi, Fukase Koichi

  New labeling probes of fluorescenced and ^<68>Ga-DOTA, as the positron emission nucleus for PET, througn rapid 6π-azaelectrocyclization were designed and synthesized, (E)-ester aldehydes 1. The high reactivity of these probes enabled the labeling of lysine residues in peptides, proteins, and even the amino groups on the cell surfaced at very low concentration (-10^<-8>M) within a short recation time (-10min) to result in "selective" and "non-destructive" labeling of the more accessible amines. The first microPET of glycoproteins, ^<68>Ga-DOTA-orosomucoid and asialoorosomucoid successfully visualized the differences in the circulatory residence of glycoproteins, in the presence or absence of the sialic acids. New N-glycan clusters with MW of 50KDa were also developed and their in vivo dynamics, being affected significantly by their glycan structures, could be visualized through the present amine-labeling & PET and/or noninvasive fluorescence imaging. The azaelectrocyclization-based biocojugation is also applicable to the engineering of the proteins and/or the cell surfaces by the oligosacchrides; the chemically engineered lymphocytes by N-glycan sussessfully traget the tumor tissue implanted in the BALB/c nude mice, based on the noninvasive fluorescence imaging.

  Symposium on the chemistry of natural products, Sep. 2010, Symposium on the Chemistry of Natural Products, symposium papers, (52) (52), 25 - 30, Japanese


• Synthesis of a ^<11>C-Labeled Flavonoid and In Vivo PET Study using Rat

  Goto Miki, Mizuma Hiroshi, Wada Yasuhiro, Onoe Hirotaka, Watanabe Yasuyoshi, Suzuki Masaaki, Doi Hisashi

  Flavonoids are orally ingested compounds, which contained ubiquitously in plant foods. Their benefits to human health are attributed to a variety of the biological activities such as antioxidant, anticarcinogenic, anti-inflammatory, immune-stimulating, and arteriosclerosis inhibiting effects etc. With the aim of in vivo molecular imaging of flavonoids by positron emission tomography (PET), we have syntehsized a PET probe of ^<11>C-labeld flavone [^<11>C]-2 in high yield by our Pd^0-mediated rapic C-[^<11>C]-methylation using [^<11>C]methyl iodide and a corresponding organoboron precursor 1. [^<11>C]-2 was intravenous injected in rat, and in vivo behavior of [^<11>C]-2 in the brain and whole body were observed by micro-PET. As results, [^<11>C]-2 penetrated the blood-brain barrier and then was accumulated in the brain at 1-5 min after the administration. On the other hand, a metabolite of ^<11>C-labeld flavone [^<11>C]-2 was accumulated in the nasal cavity. These PET images are currently in the process of analyzing, compared to the previously-reported biological activities of flavonids. Based on the synthesis of [^<11>C]-2, we intend to construct the PET prove library of flavonoids, which will be useful for development of new methodologies for disease and promotion of drug development process.

  Symposium on the chemistry of natural products, Sep. 2010, Symposium on the Chemistry of Natural Products, symposium papers, (52) (52), 259 - 264, Japanese


• PETプローブ経口投与時のPET撮像の検討

  和田 康弘, 高島 忠之, 林中 恵美, 片岡 誠, 片山 由美子, 新垣 友隆, 崔 翼龍, 山下 伸二, 渡邊 恭良

  (一社)日本核医学会, Sep. 2010, 核医学, 47(3) (3), 390 - 391, Japanese


• The increase of alpha-melanocyte-stimulating hormone in the plasma of chronic fatigue syndrome patients.

  Nobue Shishioh-Ikejima, Tokiko Ogawa, Kouzi Yamaguti, Yasuyoshi Watanabe, Hirohiko Kuratsune, Hiroshi Kiyama

  BACKGROUND: Despite extensive research, no reliable biological marker for chronic fatigue syndrome (CFS) has yet been identified. However, hyperactivation of melanotrophs in the pituitary gland and increased levels of plasma alpha-melanocyte-stimulating hormone (alpha-MSH) have recently been detected in an animal model of chronic stress. Because CFS is considered to be caused partly by chronic stress events, increased alpha-MSH plasma levels may also occur in CFS patients. We therefore examined alpha-MSH levels in CFS patients. METHODS: Fifty-five CFS patients, who were previously diagnosed within 10 years of with the disease, were enrolled in this study. Thirty healthy volunteers were studied as controls. Fasting bloods samples were collected in the morning and evaluated for their plasma levels of alpha-MSH, adrenocorticotropic hormone (ACTH), serum cortisol and dehydroepiandrosterone sulfate (DHEA-S). Mean levels of alpha-MSH were compared between the CFS and control groups using Welch's t test. RESULTS: The mean plasma alpha-MSH concentration in the CFS group (17.9 +/- 1.0 pg/mL) was significantly higher than that in healthy controls (14.5 +/- 1.0 pg/mL, p = 0.02). However, there was a wide range of values in the CFS group. The factors correlated with the plasma alpha-MSH values were analyzed using Spearman's rank correlation. A negative correlation was found between the duration of the CFS and the plasma alpha-MSH values (p = 0.04, rs = -0.28), but no correlations with ACTH, cortisol or DHEA-S levels were identified (p = 0.55, 0.26, 0.33, respectively). The CFS patients were divided into two groups: patients diagnosed for Aug. 2010, BMC neurology, 10, 73 - 73, English, International magazine

  Scientific journal


• Molecular imaging analysis of intestinal insulin absorption boosted by cell-penetrating peptides by using positron emission tomography.

  Noriyasu Kamei, Mariko Morishita, Yousuke Kanayama, Koki Hasegawa, Mie Nishimura, Emi Hayashinaka, Yasuhiro Wada, Yasuyoshi Watanabe, Kozo Takayama

  Molecular imaging technique by use of positron emission tomography (PET) is a noninvasive tool that allows one to quantitatively analyze the function of endogenous molecules and the pharmacokinetics of therapeutic agents in vivo. This technique is expected to be useful for evaluating the effectiveness of diverse drug delivery systems. We demonstrated previously that intestinal insulin absorption is increased significantly by coadministration of cell-penetrating peptides (CPPs), which are taken up effectively by several cells. However, the distribution behavior of insulin whose absorption is increased by CPPs is not clear. We used PET imaging and quantitatively analyzed the intestinal absorption and subsequent distribution of insulin and the effect of CPPs on its absorption and distribution. An unlabeled insulin solution containing tracer insulin, (68)Ga-DOTA-insulin, was administered with or without CPPs into a rat ileal closed loop. PET imaging showed that the CPPs, particularly D-R8 and L-penetratin, significantly increased the (68)Ga-DOTA-insulin level in the liver, kidney, and circulation. After absorption from the intestine, the (68)Ga-DOTA-insulin passed rapidly through the liver and accumulated in the kidney. The increase in the hepatic and renal distribution of (68)Ga-DOTA-insulin by each CPP coadministration was similar manner as that in intestinal absorption, suggesting that the increased accumulation of insulin in the liver and kidney induced by coadministration of CPPs was associated with the increased intestinal absorption of insulin. This is the first study to show that PET imaging enables one to quantitatively analyze the distribution behavior of intestinally absorbed insulin in several organs. This imaging methodology is likely to be useful for developing effective drug delivery systems targeted to specific organs.

  Aug. 2010, Journal of controlled release : official journal of the Controlled Release Society, 146(1) (1), 16 - 22, English, International magazine

  Scientific journal


• A new hypothesis of chronic fatigue syndrome: co-conditioning theory.

  Masaaki Tanaka, Yasuyoshi Watanabe

  Chronic fatigue syndrome is an illness characterized by a profound, disabling, and unexplained sensation of fatigue lasting at least 6 months, which severely impairs daily functioning and is accompanied by a combination of non-specific symptoms. Many potential causes of chronic fatigue syndrome have been investigated, including viral infections, immune dysfunctions, abnormal neuroendocrine responses, central nervous system abnormalities, autonomic dysfunctions, impaired exercise capacities, sleep disruptions, genetic backgrounds, psychiatric abnormalities, personality, and abnormal psychological processes. However, no etiology, specific physical signs or laboratory test abnormalities have been found. It is essential to establish a conceptual theory of chronic fatigue syndrome that can explain its pathophysiology in order to identify the clinical entity and to develop effective treatment methods. In this article, a new conceptual hypothesis about the pathophysiology of chronic fatigue syndrome, the co-conditioning theory, is presented: after repetitive overwork and/or stress, alarm signal to rest and fatigue sensation may cause in response to an unconditioned stimulus (impaired homeostasis and function) that has been paired with a conditioned stimulus (overwork and/or stress). In the future, a new treatment strategy for patients with chronic fatigue syndrome, re-co-conditioning therapy, may be developed on the basis of the co-conditioning theory. In addition, this theory will likely contribute to a better understanding of the pathophysiology of chronic fatigue syndrome.

  Aug. 2010, Medical hypotheses, 75(2) (2), 244 - 9, English, International magazine

  Scientific journal


• 片頭痛病態モデルラットを用いた疼痛伝達回路の解析(Analysis of nociceptive pathway in a rat model of migraine using small-animal PET)

  崔 翼龍, 佐古 健生, 豊田 浩士, 奥山 香里, 尾上 嘉代, 林中 恵美, 和田 康弘, 渡辺 恭良, 片岡 洋祐

  日本神経化学会, Aug. 2010, 神経化学, 49(2-3) (2-3), 757 - 757, English


• Establishment of in vivo brain imaging method in conscious mice.

  Hiroshi Mizuma, Miho Shukuri, Takuya Hayashi, Yasuyoshi Watanabe, Hirotaka Onoe

  UNLABELLED: In vivo imaging, such as PET, requires restriction of body movements and is generally conducted under sedation by anesthetic agents in studies using laboratory animals. Because anesthetics reduce neural activity and metabolism, physiologic neural functions are difficult to assess in animal PET studies. Therefore, use of an appropriate method in conscious animals is important and is a practical requirement for physiologic in vivo brain imaging studies. Here, we established an in vivo imaging system for conscious mice to reveal the physiologic regional cerebral glucose metabolic rate (rCMRglu) with (18)F-FDG PET. METHODS: We first developed a head holder to enable brain PET of a conscious mouse. To obtain optimal rCMRglu, we examined the effects of physical and psychologic stresses caused by ambient temperature, intravenous injection, and acclimation to the apparatus and immobile state. Finally, quantitative kinetic analysis was performed for rCMRglu based on a 2-tissue-compartment model with an input function of arterial blood sampling under both conscious and anesthetized (1.5% isoflurane) conditions. RESULTS: Increasing the ambient temperature increased uptake of (18)F-FDG in the brain significantly while reducing the uptake in skeletal muscle and brown adipose tissue that was caused by shivering. The reduction of brain (18)F-FDG uptake caused by tail holding and manual injection was significantly ameliorated by the use of an automated slow injection. Although brain uptake of (18)F-FDG varied at the first session of PET, uptake at the second and subsequent sessions was stable, even after long-term acclimation. After these beneficial changes, brain uptake of (18)F-FDG improved significantly, to approximately 260% above the preconditioned state, which is comparable with that obtained in mice that have been allowed to move freely about their home cages. Quantitative kinetic analyses revealed that isoflurane anesthesia lowered rCMRglu in the cerebral cortex, striatum, thalamus, and cerebellum by 66%, 59%, 62%, and 22%, respectively, mainly by reducing the k(3) value, a rate constant for phosphorylation by hexokinase. CONCLUSION: To our knowledge, this is the first study to report quantitative kinetic analysis of rCMRglu in mice that have been conscious throughout PET. This investigation will open avenues for research into in vivo functional brain molecular imaging in both normal and genetically manipulated mice.

  Jul. 2010, Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 51(7) (7), 1068 - 75, English, International magazine

  Scientific journal


• 抗体医薬におけるmolecular imaging

  長谷川 功紀, 渡辺 恭良

  (有)科学評論社, Jul. 2010, 腫瘍内科, 6(1) (1), 86 - 92, Japanese


• Anti-fatigue effect of dicethiamine hydrochloride is likely associated with excellent absorbability and high transformability in tissues as a Vitamin B(1).

  Toshikatsu Shimizu, Hiroshi Hoshino, Shugo Nishi, Satoshi Nozaki, Yasuyoshi Watanabe

  The anti-fatigue effect of dicethiamine hydrochloride (DCET) was assessed and compared to that of thiamine hydrochloride (VB(1)HCl) in rats. The absorbability and tissue distribution of thiamine after oral administration of DCET and VB(1)HCl were also examined. To create fatigued animals, male SD rats were placed in plastic cages containing 1.5cm of water for 5 consecutive days. The extent of fatigue was evaluated by a weight-loaded forced swimming test. After oral administration of DCET or VB(1)HCl to non-fatigued rats, blood and tissues were serially collected to determine the concentrations of thiamine and its phosphate esters. Pharmacokinetic analysis was performed to examine the thiamine profile in the body after administration of DCET or VB(1)HCl. Swimming time was significantly shorter for the fatigued vehicle group than the non-fatigued group. DCET (30 and 100mg/kg) significantly prolonged the swimming time compared to the fatigued vehicle group. The anti-fatigue effect of VB(1)HCl (70.1mg/kg) was not significant in our set of results. Both DCET and VB(1)HCl were rapidly absorbed into the circulating blood as thiamine and eventually became localized in the organs. Thiamine was distributed at higher concentrations to the blood, heart, thigh muscles, cerebellum, hippocampus, and thalamus after administration of DCET compared to VB(1)HCl. These results indicate that DCET is a vitamin B(1) derivative that has excellent absorbability and transformability in tissues and suggest that DCET as an oral therapy may be useful against combined mental and physical fatigue, such as that often encountered in contemporary society.

  Jun. 2010, European journal of pharmacology, 635(1-3) (1-3), 117 - 23, English, International magazine

  Scientific journal


• Electrocyclization-based labeling allows efficient in vivo imaging of cellular trafficking.

  Katsunori Tanaka, Kaori Minami, Tsuyoshi Tahara, Yohei Fujii, Eric R O Siwu, Satoshi Nozaki, Hirotaka Onoe, Satomi Yokoi, Koichi Koyama, Yasuyoshi Watanabe, Koichi Fukase

  Jun. 2010, ChemMedChem, 5(6) (6), 841 - 5, English, International magazine

  Scientific journal


• A functional polymorphism in the disrupted-in schizophrenia 1 gene is associated with chronic fatigue syndrome.

  Sanae Fukuda, Ryota Hashimoto, Kazutaka Ohi, Kouzi Yamaguti, Yasuhito Nakatomi, Yuka Yasuda, Kouzin Kamino, Masatoshi Takeda, Seiki Tajima, Hirohiko Kuratsune, Yoshiki Nishizawa, Yasuyoshi Watanabe

  AIMS: Disrupted-in schizophrenia 1 (DISC1), identified in a pedigree with a familial psychosis with the chromosome translocation (1:11), is a putative susceptibility gene for psychoses such as schizophrenia and major depressive disorder (MDD). Patients with chronic fatigue syndrome (CFS) report having continuous severe fatigue and many overlapping symptoms with MDD; however, the mechanism and effective treatment of CFS are still unclear. We focused on the overlapping symptoms between CFS and MDD and performed an association study of the functional single-nucleotide polymorphism (SNP) in the DISC1 gene with CFS. MAIN METHODS: Venous blood was drawn from CFS patients and controls and genomic DNA was extracted from the whole blood according to standard procedures. Ser704Cys DISC1 SNP was genotyped using the TaqMan 5'-exonuclease allelic discrimination assay. KEY FINDINGS: We found that the Cys704 allele of Ser704Cys SNP was associated with an increased risk of CFS development compared with the Ser704 allele. SIGNIFICANCE: DISC1 Ser704Cys might be a functional variant that affects one of the mechanisms implicated in the biology of CFS. Some patients with CFS showed a phenotype similar to that of patients with MDD, but further studies are needed to clarify the biological mechanism, because this study is of a rather preliminary nature. Despite the variety of patients with CFS, DISC1 Ser704Cys has an association with CFS, which may also suggest that DISC1 plays a central role in the induction of various psychiatric diseases.

  May 2010, Life sciences, 86(19-20) (19-20), 722 - 5, English, International magazine

  Scientific journal


• PETを用いた緑内障早期診断法の確立

  嶋澤 雅光, 井口 勇太, 伊藤 保志, 山中 創, 林 拓也, 季 斌, 樋口 真人, 須原 哲也, 今村 一之, 新家 眞, 渡辺 恭良, 尾上 浩隆, 原 英彰

  日本分子イメージング学会, May 2010, JSMI Report, 3(2) (2), 138 - 138, Japanese

  [Refereed]


• 緑内障視神経障害モデル動物における拡散テンソル画像

  林 拓也, 原 英彰, 嶋澤 雅光, 井口 勇太, 伊藤 保志, 合瀬 恭幸, 飯田 英博, 山中 創, 渡辺 恭良, 尾上 浩隆

  日本分子イメージング学会, May 2010, JSMI Report, 3(2) (2), 102 - 102, Japanese

  [Refereed]


• General method for the (11)C-labeling of 2-arylpropionic acids and their esters: construction of a PET tracer library for a study of biological events involved in COXs expression.

  Misato Takashima-Hirano, Miho Shukuri, Tadayuki Takashima, Miki Goto, Yasuhiro Wada, Yasuyoshi Watanabe, Hirotaka Onoe, Hisashi Doi, Masaaki Suzuki

  Cyclooxygenase (COX) is a critical enzyme in prostaglandin biosynthesis that modulates a wide range of biological functions, such as pain, fever, and so on. To perform in vivo COX imaging by positron emission tomography (PET), we developed a method to incorporate (11)C radionuclide into various 2-arylpropionic acids that have a common methylated structure, particularly among nonsteroidal anti-inflammatory drugs (NSAIDs). Thus, we developed a novel (11)C-radiolabeling methodology based on rapid C-[(11)C]methylation by the reaction of [(11)C]CH(3)I with enolate intermediates generated from the corresponding esters under basic conditions. One-pot hydrolysis of the above [(11)C]methylation products also allows the synthesis of desired (11)C-incorporated acids. We demonstrated the utility of this method in the syntheses of six PET tracers, [(11)C]Ibuprofen, [(11)C]Naproxen, [(11)C]Flurbiprofen, [(11)C]Fenoprofen, [(11)C]Ketoprofen, and [(11)C]Loxoprofen. Notably, we found that their methyl esters were particularly useful as proradiotracers for a study of neuroinflammation. The microPET studies of rats with lipopolysaccharide (LPS)-induced brain inflammation clearly showed that the radioactivity of PET tracers accumulated in the inflamed region. Among these PET tracers, the specificity of [(11)C]Ketoprofen methyl ester was demonstrated by a blocking study. Metabolite analysis in the rat brain revealed that the methyl esters were initially taken up in the brain and then underwent hydrolysis to form pharmacologically active forms of the corresponding acids. Thus, we succeeded in general (11)C-labeling of 2-arylpropionic acids and their methyl esters as PET tracers of NSAIDs to construct a potentially useful PET tracer library for in vivo imaging of inflammation involved in COXs expression.

  Apr. 2010, Chemistry (Weinheim an der Bergstrasse, Germany), 16(14) (14), 4250 - 8, English, International magazine

  Scientific journal


• Personality and fatigue in medical students.

  Masaaki Tanaka, Kei Mizuno, Sanae Fukuda, Yasuyoshi Watanabe

  Among medical students, fatigue is a common complaint and is related to poor academic outcomes. Associations of scores on personality traits and fatigue in medical students were examined. A group of 125 healthy second-year medical students completed a questionnaire about fatigue, the Japanese version of the Chalder Fatigue Scale, and the Temperament and Character Inventory. On simple regression analyses, the Temperament and Character Inventory dimension of Harm Avoidance was positively associated with Fatigue scores and those on Self-directedness were negatively associated. Similarly, on multiple regression analyses adjusted for age and sex, scores on the Temperament and Character Inventory dimension of Harm Avoidance were positively associated with Fatigue scores, and those for Self-directedness were negatively associated. These correlations were evident even after adjustment for other Temperament and Character Inventory dimensions. The temperament dimension of Harm Avoidance and the character dimension of Self-directedness were both associated with Fatigue in medical students.

  Apr. 2010, Psychological reports, 106(2) (2), 567 - 75, English, International magazine

  Scientific journal


• Fatigue is a predictor for cardiovascular outcomes in patients undergoing hemodialysis.

  Koyama H, Fukuda S, Shoji T, Inaba M, Tsujimoto Y, Tabata T, Okuno S, Yamakawa T, Okada S, Okamura M, Kuratsune H, Fujii H, Hirayama Y, Watanabe Y, Nishizawa Y

  BACKGROUND AND OBJECTIVES: Despite potential significance of fatigue and its underlying components in the occurrence of cardiovascular diseases, epidemiologic data showing the link are virtually limited. This study was designed to examine whether fatigue symptoms or fatigue's underlying components are a predictor for cardiovascular diseases in high-risk subjects with ESRD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: 788 volunteer patients under hemodialysis therapy (506 male, 282 female) completed the survey between October and November 2005, with the follow-up period up to 26 months to monitor occurrence of fatal or nonfatal cardiovascular events. The questionnaire consisted of 64 questions, and promax rotation analysis of the principal component method conceptualized eight fatigue-related factors: fatigue itself, anxiety and depression, loss of attention and memory, pain, overwork, autonomic imbalance, sleep problems, and infection. RESULTS: 14.7% of the patients showed fatigue scores higher than twice the SD of the mean for healthy volunteers. These highly fatigued patients exhibited a significantly higher risk for cardiovascular events (hazard ratio: 2.17; P < 0.01), with the relationship independent of the well-known risk factors, including age, diabetes, cardiovascular disease history, and inflammation and malnutrition markers. Moreover, comparisons of the risk in key subgroups showed that the risk of high fatigue score for cardiovascular events was more prominent in well-nourished patients, including lower age, absence of past cardiovascular diseases, higher serum albumin, and high non-HDL cholesterol. CONCLUSIONS: Fatigue can be an important predictor for cardiovascular events in patients with ESRD, with the relationship independent of the nutritional or inflammatory status.

  Apr. 2010, Clinical journal of the American Society of Nephrology : CJASN, 5(4) (4), 659 - 666, English, International magazine

  [Refereed]

  Scientific journal


• A Combined 6 pi-Azaelectrocyclization/Staudinger Approach to Protein and Cell Engineering: Noninvasive Tumor Targeting by N-Glycan-Engineered Lymphocytes

  Katsunori Tanaka, Kaori Minami, Tsuyoshi Tahara, Eric R. O. Siwu, Koichi Koyama, Satoshi Nozaki, Hirotaka Onoe, Yasuyoshi Watanabe, Koichi Fukase

  2010, JOURNAL OF CARBOHYDRATE CHEMISTRY, 29(3) (3), 118 - 132, English

  [Refereed]

  Scientific journal


• Premorbid personality in chronic fatigue syndrome as determined by the Temperament and Character Inventory.

  Sanae Fukuda, Hirohiko Kuratsune, Seiki Tajima, Shoko Takashima, Kouzi Yamagutchi, Yoshiki Nishizawa, Yasuyoshi Watanabe

  BACKGROUND: Using the Temperament and Character Inventory (TCI), we examined personality characteristics in patients with chronic fatigue syndrome (CFS) compared with healthy control subjects, and CFS patients with and without psychiatric diseases. There have been no previous reports assessing personality in CFS patients using the TCI. METHODS: A total of 211 CFS patients and 90 control subjects completed the TCI and the Chalder Fatigue Scale questionnaires. RESULTS: Compared with control subjects, CFS patients demonstrated significantly lower premorbid Novelty Seeking, and higher Harm Avoidance and persistence. The fatigue score for CFS patients with psychiatric diseases was higher than that for CFS patients without psychiatric diseases. Patients with CFS with psychiatric diseases showed lower premorbid Self-Directedness when compared with CFS patients without psychiatric diseases. The fatigue score was negatively correlated with premorbid Self-Directedness and Cooperativeness, and positively correlated with Harm Avoidance among CFS patients. CONCLUSION: This study supported the stereotyped image of CFS patients as perfectionists, which is similar to the Persistence score, and neurotics, which is similar to the Harm Avoidance score. Patients displaying greater neuroticisms and poorer social and communication skills, similar to the Self-Directedness and Cooperativeness scores, tend to have intercurrent psychiatry diseases and show more severe symptoms of CFS.

  2010, Comprehensive psychiatry, 51(1) (1), 78 - 85, English, International magazine

  Scientific journal


• Effects of mild-stream bathing on recovery from mental fatigue.

  Kei Mizuno, Masaaki Tanaka, Kanako Tajima, Naoki Okada, Kazumasa Rokushima, Yasuyoshi Watanabe

  BACKGROUND: Bathing in hot water is very common in Japan; people bathe in order to clean their bodies and to recover from physical and mental fatigue. However, there have been few reports examining the effects of bathing on recovery from mental fatigue. The purpose of this study was to examine the effects of mild-stream bathing on recovery from mental fatigue. MATERIAL/METHODS: During mild-stream bathing, a mild stream continuously passes from the sole to the calf, thigh, waist and back, thus providing a massage function. In a double-blinded, placebo-controlled, crossover experiment, 14 male healthy volunteers were randomized into normal bathing and mild-stream bathing experiments. After a fatigue-inducing mental task for 4 hours, subjects took a normal or mild-stream bath. RESULTS: Heart rate was higher, muscle stiffness in the waist was lower and plasma cortisol levels tended to be lower after mild-stream bathing when compared to normal bathing. In addition, after mild-stream bathing, mental task performance, as assessed by reaction times on an advanced trail making test, was better than that after normal bathing. CONCLUSIONS: The present results suggest that improved working memory processing, diminished waist muscle tone, and attenuated mental stress are induced by mild-stream bathing. Therefore, mild-stream bathing appears to be more effective for alleviating mental fatigue than normal bathing.

  Jan. 2010, Medical science monitor : international medical journal of experimental and clinical research, 16(1) (1), CR8-14, English, International magazine

  Scientific journal


• Temperament and character as predictors of fatigue-induced symptoms among school children in Japan: a 1-year follow-up study.

  Emi Yamano, Sanae Fukuda, Takako Joudoi, Kei Mizuno, Masaaki Tanaka, Yosky Kataoka, Junko Kawatani, Miyuki Takano, Akemi Tomoda, Kyoko Imai-Matsumura, Teruhisa Miike, Fumihiko Matsuda, Yasuyoshi Watanabe

  OBJECTIVE: This 1-year follow-up study was performed to examine the association of temperament and character dimensions with new onset of fatigue-induced symptoms among school children in Japan, focusing on the transition from childhood to early adolescence. METHOD: This study prospectively reviewed data from 1512 school children from four elementary and four junior high schools in Japan. The survey was conducted in 2006 and 2007. Multivariate logistic regression analyses were performed to examine the association of psychological dimensions, assessed by the Junior Temperament and Character Inventory, with fatigue-induced symptoms. RESULTS: The correlation between temperament and character dimensions with new-onset of fatigue-induced symptoms differed as the students advanced into higher grades. In terms of physical symptoms in males, traits correlated with fatigue-induced symptoms included Novelty Seeking (headaches OR, 1.36; 95% CI, 1.07-1.73) or Reward Dependence (extreme tiredness OR, 1.84; 95% CI, 1.09-3.12; muscle weakness OR, 2.32; 95% CI, 1.28-4.20) during elementary school, whereas in females, Novelty Seeking was mainly associated with both physical (morning fatigue OR, 1.40; 95% CI, 1.10-1.77; headaches OR, 1.22; 95% CI, 1.04-1.43) and mental (mood changes OR, 1.30; 95% CI, 1.09-1.56) symptoms. Among ninth graders, more mental symptoms of fatigue were associated with Harm Avoidance (males, poor motivation OR, 1.20; 95% CI, 1.02-1.42; females, mood changes OR, 1.25; 95% CI, 1.06-1.49) and Self Directedness (males, poor motivation OR, 0.75; 95% CI, 0.59-0.96; females, difficulty thinking OR, 0.78; 95% CI, 0.62-0.98). CONCLUSION: Confirmation that the correlation between personality traits and fatigue-induced symptoms changes with grade at school has implications for screening susceptible children and adolescents and may help prevent the occurrence of such symptoms at an early stage.

  2010, Comprehensive psychiatry, 51(3) (3), 256 - 65, English, International magazine

  Scientific journal


• Effort-reward imbalance for learning is associated with fatigue in school children.

  Sanae Fukuda, Emi Yamano, Takako Joudoi, Kei Mizuno, Masaaki Tanaka, Junko Kawatani, Miyuki Takano, Akemi Tomoda, Kyoko Imai-Matsumura, Teruhisa Miike, Yasuyoshi Watanabe

  We examined relationships among fatigue, sleep quality, and effort-reward imbalance for learning in school children. We developed an effort-reward for learning scale in school students and examined its reliability and validity. Self-administered surveys, including the effort reward for leaning scale and fatigue scale, were completed by 1,023 elementary school students (grades 4-6) and 1,361 junior high school students (grades 7-9) at the end of 2006. Effort-reward imbalance for learning was associated with a high incidence of fatigue and sleep problems in elementary and junior high school students of both genders. A good relationship with family was associated with a low fatigue score in junior high school boys, and a good relationship with friends was associated with a low fatigue score in junior high school girls by multiple regression analysis. Fatigue score was associated with effort-reward imbalance and fatigue and quality of sleep in schoolchildren. Fatigue may lead to a decline in school performance, negative health outcomes, or refusal to attend school. These results suggest that it is desirable to consider social support, quality of sleep, and effort-reward imbalance when managing fatigue in school children.

  2010, Behavioral medicine (Washington, D.C.), 36(2) (2), 53 - 62, English, International magazine

  Scientific journal


• Relationship between fatigue and photosensitivity.

  Yoshihito Shigihara, Masaaki Tanaka, Yasuyoshi Watanabe

  It is considered that photosensitivity is one of the most important factors to cause video-game epilepsy. Since photosensitivity is thought to cause various signs of hypersensitivity in the central nervous system and hypersensitivity is believed to be related to fatigue, whether fatigue is associated with photosensitivity was determined. The study group consisted of 68 healthy medical students attending Osaka City University Graduate School of Medicine. They completed questionnaires dealing with fatigue (Chalder Fatigue Scale) and photosensitivity. On simple regression analyses, fatigue score was positively associated with photosensitivity score. Similarly, on multiple regression analyses adjusted for age, gender, and sleeping hours, fatigue score was positively associated with photosensitivity score. Fatigue is associated with photosensitivity. Our findings provide new perspectives on fatigue.

  2010, Behavioral medicine (Washington, D.C.), 36(4) (4), 109 - 12, English, International magazine

  Scientific journal


• Medial orbitofrontal cortex is associated with fatigue sensation

  Seiki Tajima, Shigeyuki Yamamoto, Masaaki Tanaka, Yosky Kataoka, Masao Iwase, Etsuji Yoshikawa, Hiroyuki Okada, Hirotaka Onoe, Hideo Tsukada, Hirohiko Kuratsune, Yasuomi Ouchi, Yasuyoshi Watanabe

  Hindawi Publishing Corporation, 2010, Neurology Research International, 2010, 1421 - 1425, English, International magazine

  [Refereed]

  Scientific journal


• High striatal amyloid beta-peptide deposition across different autosomal Alzheimer disease mutation types.

  Victor L Villemagne, Suzuka Ataka, Toshiki Mizuno, William S Brooks, Yasuhiro Wada, Masaki Kondo, Gareth Jones, Yasuyoshi Watanabe, Rachel Mulligan, Masanori Nakagawa, Takami Miki, Hiroyuki Shimada, Graeme J O'Keefe, Colin L Masters, Hiroshi Mori, Christopher C Rowe

  BACKGROUND: Supported by compelling genetic data regarding early-onset familial Alzheimer disease (AD), the amyloid beta-peptide (Abeta)-centric theory holds that Abeta is involved in the pathogenesis of sporadic AD. Mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes lead to increased Abeta levels before symptoms arise. OBJECTIVES: To evaluate the pattern of Pittsburgh Compound B (PiB) retention in subjects with different autosomal dominant mutations associated with familial AD vs that in healthy age-matched control subjects and subjects with probable sporadic AD, to correlate Abeta burden as measured by PiB with available clinical and cognitive data, and to compare the regional brain patterns of PiB retention and fluorodeoxyglucose F 18 (FDG) uptake. DESIGN: Correlation analysis of positron emission tomography (PET) imaging studies. SETTING: Academic research. PARTICIPANTS: Seven PSEN1 mutation carriers and 1 APP mutation carrier underwent PiB and FDG PET imaging. Amyloid beta-peptide burden and FDG uptake were established using standardized uptake values normalized to pons. MAIN OUTCOME MEASURE: Primary outcomes were PET results, which were compared with those of a well-characterized cohort of 30 healthy control subjects and 30 subjects with probable sporadic AD. RESULTS: All mutation carriers had high PiB retention in the striatum, with some also having cortical PiB retention in ventrofrontal and posterior cingulate/precuneus areas. The striatal pattern of PiB retention was similar in the PSEN1 and APP mutation carriers. Neither striatal nor cortical Abeta burden was related to cognitive status. CONCLUSIONS: Consistent with previous studies, the pattern of Abeta deposition in familial AD differs from that in sporadic AD, with higher striatal and somewhat lower cortical PiB retention in familial AD. The pattern and degree of Abeta deposition were not associated with mutation type nor cognitive status.

  Dec. 2009, Archives of neurology, 66(12) (12), 1537 - 44, English, International magazine

  Scientific journal


• Thiamine tetrahydrofurfuryl disulfide improves energy metabolism and physical performance during physical-fatigue loading in rats

  Satoshi Nozaki, Hiroshi Mizuma, Masaaki Tanaka, Guanghua Jin, Tsuyoshi Tahara, Kei Mizuno, Masanori Yamato, Kaori Okuyama, Asami Eguchi, Kouji Akimoto, Takahito Kitayoshi, Noriko Mochizuki-Oda, Yosky Kataoka, Yasuyoshi Watanabe

  Dec. 2009, NUTRITION RESEARCH, 29(12) (12), 867 - 872, English, International magazine

  [Refereed]

  Scientific journal


• 15R-[11C]TICを用いたPositron Emission Tomography(PET)による肝胆系輸送の機能評価

  高島 忠之, 長田 浩子, 中江 崇敬, 橋爪 良信, 土居 久志, 和田 康弘, 崔 翼龍, 鈴木 正昭, 渡辺 恭良, 北村 吏司, 前田 和哉, 楠原 洋之, 杉山 雄一

  ライフサイエンス出版(株), Dec. 2009, 薬理と治療, 37(Suppl.1) (Suppl.1), S - 69, Japanese


• PETプローブ15R-[11C]TICの肝胆系輸送に関与するトランスポーターの同定ならびにヒト相互作用試験時の血漿・肝臓内濃度変動およびin vitro試験からの予測

  杉山 雄一, 北村 吏司, 前田 和哉, 楠原 洋之, 高島 忠之, 長田 浩子, 橋爪 良信, 土居 久志, 中江 崇敬, 和田 康弘, 崔 翼龍, 鈴木 正昭, 渡辺 恭良

  ライフサイエンス出版(株), Dec. 2009, 薬理と治療, 37(Suppl.1) (Suppl.1), S - 78, Japanese


• C-11-PK11195 PET for the In Vivo Evaluation of Neuroinflammation in the Rat Brain After Cortical Spreading Depression

  Yilong Cui, Tadayuki Takashima, Misato Takashima-Hirano, Yasuhiro Wada, Miho Shukuri, Yasuhisa Tamura, Hisashi Doi, Hirotaka Onoe, Yosky Kataoka, Yasuyoshi Watanabe

  Nov. 2009, JOURNAL OF NUCLEAR MEDICINE, 50(11) (11), 1904 - 1911, English, International magazine

  [Refereed]

  Scientific journal


• The risk of exaggerated risk aversion-a life and death struggle for molecular imaging.

  Bengt Långström, Anders Grahnen, Per Hartvig Honoré, Jürgen Borlak, Mats Bergstrom, Bengt Nielsen, Jeanluc Vanderheyden, Yasuyoshi Watanabe, Raymond Josephsson, Poul F Høilund-Carlsen, Markus Schwaiger, Steven M Larson, David M Goldenberg, Andreas Melzer, Henry Engler, Rodney Hicks, Anders Sundin, Marko Seppänen, Göran Hedenstierna, Agneta Nordberg, David Brooks

  Oct. 2009, European journal of nuclear medicine and molecular imaging, 36(10) (10), 1693 - 4, English, International magazine


• 11Cで標識した非ステロイド性抗炎症薬(NSAIDs)によるPETイメージング

  宿里 充穂, 高島 好聖, 徳田 景子, 佐古 健生, 崔 翼龍, 後藤 美樹, 土居 久志, 鈴木 正昭, 渡辺 恭良, 尾上 浩隆

  (一社)日本核医学会, Sep. 2009, 核医学, 46(3) (3), 319 - 320, Japanese


• Increased cerebral uptake of [18F]fluoro-deoxyglucose but not [1-14C]glucose early following traumatic brain injury in rats.

  Niklas Marklund, Sven Sihver, David A Hovda, Bengt Långström, Yasuyoshi Watanabe, Gunnar Ronquist, Mats Bergström, Lars Hillered

  Following experimental and clinical traumatic brain injury (TBI), the local cerebral metabolic rate of glucose (lCMR(Glc)) is commonly estimated using the 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG) method. The adequate estimation of lCMR(Glc) using FDG requires a correction factor, the lumped constant (LC), to convert FDG net uptake into lCMR(Glc). The LC, and thus lCMR(Glc) calculations, require a steady-state that may be disrupted following TBI. In the present report, we hypothesized that [1-(14)C]glucose uptake would accurately reflect glucose dynamics early post-injury, and was compared to the regional uptake of FDG in 44 rats subjected to moderate (2.4-2.6 atm) lateral fluid percussion brain injury (FPI) or sham injury. Cortical energy state and adenylate (ATP, ADP, and AMP) levels were also measured. Early (7-42 min) after FPI, FDG uptake was increased in the ipsilateral cortex and hippocampus (p < 0.05). In contrast, no change in [1-(14)C]glucose uptake (7 and 17 min post-injury) or cortical adenylate content (42 min post-injury) was observed. At 12 h following FPI, the ipsilateral FDG and [1-(14)C]glucose uptake were decreased in the cortex and hippocampus, and the ipsilateral cortical ATP concentration was decreased in comparison to sham-injured controls (p < 0.05). Under the present experimental conditions, the rate of cerebral uptake of FDG and of [1-(14)C]glucose differed, and indicated that following TBI, regional changes in the LC may occur in the immediate, but not in the late, post-injury phase. These results should be considered when interpreting results obtained using FDG for the estimation of lCMR(Glc) early following experimental TBI.

  Aug. 2009, Journal of neurotrauma, 26(8) (8), 1281 - 93, English, International magazine

  Scientific journal


• Evaluation of Intestinal Absorption Kinetics after Oral Administration Using Positron Emission Tomography (PET)

  Tadayuki Takashima, Makoto Kataoka, Shunichi Kitajima, Machiko Murai, Hiroyuki Ou, Yasuhiro Wada, Emi Hayashinaka, Yilong Cui, Shinji Yamashita, Yasuyoshi Watanabe

  Aug. 2009, DRUG METABOLISM REVIEWS, 41, 66 - 67, English

  [Refereed]


• Chronic stress elicits prolonged activation of alpha-MSH secretion and subsequent degeneration of melanotroph.

  Tokiko Ogawa, Nobue Shishioh-Ikejima, Hiroyuki Konishi, Tetsuya Makino, Hiroyoshi Sei, Sumiko Kiryu-Seo, Masaaki Tanaka, Yasuyoshi Watanabe, Hiroshi Kiyama

  Prolonged stress affects homeostasis in various organs and induces stress-associated disorders. We examined the cellular changes of pituitary gland under the continuous stress condition using a rat model in which rats were kept in a cage filled with water to a height of 1.5 cm for up to 5 days. Among the pituitary hormone mRNAs, proopiomelanocortin mRNA was up-regulated specifically in the intermediate lobe (IL) of this rat model. Additionally, the peripheral blood levels of alpha-melanocyte stimulating hormone (alpha-MSH), a major product of proopiomelanocortin in IL were increased. The alpha-MSH secreting cells, melanotrophs, showed a markedly developed endoplasmic reticulum and Golgi apparatus in the early phase of the experiment. Subsequent continuous stress caused remarkable dilation of the endoplasmic reticulum, disruption of the Golgi structure, and the degeneration of some melanotrophs. In addition the dopaminergic nerve fibers from hypothalamus were markedly decreased in IL. A dopamine antagonist elicited the similar morphologic changes of melanotroph in normal rat. These findings suggest that prolonged stress suppressed hypothalamus-derived dopamine release in IL, which elicited over-secretion of alpha-MSH from the melanotrophs. The present study also suggests that prolonged hyperactivation of endocrine cells could lead to disorder of secretion mechanisms and eventual degeneration.

  Jun. 2009, Journal of neurochemistry, 109(5) (5), 1389 - 99, English, International magazine

  Scientific journal


• Changes in plasma and tissue amino acid levels in an animal model of complex fatigue.

  Guanghua Jin, Yosky Kataoka, Masaaki Tanaka, Hiroshi Mizuma, Satoshi Nozaki, Tsuyoshi Tahara, Kei Mizuno, Masanori Yamato, Yasuyoshi Watanabe

  OBJECTIVE: Fatigue can be classified as physical or mental, depending on its cause. In physical fatigue, changes in the plasma levels of some amino acids have been reported. However, complex fatigue, which is experienced in daily life, is a combination of physical and mental fatigue. We aimed to identify changes in amino acid levels in the plasma, skeletal muscle, liver, and brain in an animal model of complex fatigue. METHODS: Rats were kept in a cage filled with water to a height of 2.2 cm for 5 d. Because rats showed a reduction of body weight when the model was developed, we also included a food-restricted group showing a similar profile in weight reduction as the water-immersed rats. A non-treated control group was also included. RESULTS: Results indicated that levels of branched-chain amino acids (valine, leucine, and isoleucine) were increased in plasma (valine, leucine, and isoleucine; P < 0.01), skeletal muscle (valine, leucine, and isoleucine; P < 0.01), the liver (valine; P < 0.05), and brain (isoleucine; P < 0.05), whereas a reduction in other amino acid levels (total amino acids and glutamine in the plasma, skeletal muscle, and liver; and phenylalanine, tyrosine, arginine, and threonine in the brain; P < 0.01) was seen in animals with complex fatigue. CONCLUSION: Complex fatigue may bring about systemic changes in amino acid metabolism in multiple organs.

  May 2009, Nutrition (Burbank, Los Angeles County, Calif.), 25(5) (5), 597 - 607, English, International magazine

  Scientific journal


• Personality traits associated with intrinsic academic motivation in medical students.

  Masaaki Tanaka, Kei Mizuno, Sanae Fukuda, Seiki Tajima, Yasuyoshi Watanabe

  OBJECTIVES: Motivation is one of the most important psychological concepts in education and is related to academic outcomes in medical students. In this study, the relationships between personality traits and intrinsic academic motivation were examined in medical students. METHODS: The study group consisted of 119 Year 2 medical students at Osaka City University Graduate School of Medicine. They completed questionnaires dealing with intrinsic academic motivation (the Intrinsic Motivation Scale toward Learning) and personality (the Temperament and Character Inventory [TCI]). RESULTS: On simple regression analyses, the TCI dimensions of persistence, self-directedness, co-operativeness and self-transcendence were positively associated with intrinsic academic motivation. On multiple regression analysis adjusted for age and gender, the TCI dimensions of persistence, self-directedness and self-transcendence were positively associated with intrinsic academic motivation. CONCLUSIONS: The temperament dimension of persistence and the character dimensions of self-directedness and self-transcendence are associated with intrinsic academic motivation in medical students.

  Apr. 2009, Medical education, 43(4) (4), 384 - 7, English, International magazine

  Scientific journal


• No apparent difference in the prevalence of parvovirus B19 infection between chronic fatigue syndrome patients and healthy controls in Japan.

  Yukiko Hakariya Kato, Masanobu Yamate, Muneo Tsujikawa, Hiromi Nishigaki, Yukie Tanaka, Mikihiro Yunoki, Hirohiko Kuratsune, Yasuyoshi Watanabe, Kazuyoshi Ikuta

  Mar. 2009, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology, 44(3) (3), 246 - 7, English, International magazine


• Daily oral administration of crocetin attenuates physical fatigue in human subjects.

  Hiroshi Mizuma, Masaaki Tanaka, Satoshi Nozaki, Kei Mizuno, Tsuyoshi Tahara, Suzuka Ataka, Tomohiro Sugino, Tomoko Shirai, Yoshitaka Kajimoto, Hirohiko Kuratsune, Osami Kajimoto, Yasuyoshi Watanabe

  This study compared the effects of placebo with a carotenoid compound, crocetin, as well as an antioxidant, ascorbic acid, on physical fatigue in humans. In this double-blind, placebo-controlled, 3-way crossover study, 14 Japanese healthy volunteers (7 men and 7 women) were randomized to oral administration of crocetin (15 mg), ascorbic acid (3,000 mg), or placebo for 8 days. Subjects performed workload tests on a bicycle ergometer at fixed workloads for 120 minutes at 2 times (a total of 240 minutes) as a fatigue-inducing physical task. During the physical task, subjects performed nonworkload tests at maximum velocity (MV) of 10 seconds at 30 minutes (30-minute test) after the start of the physical task and at 30 minutes before the end of the task (210-minute test). The change in MV from the 30- to the 210-minute test was significantly higher in men who received crocetin compared with men who received placebo (P < .05). This effect of crocetin was specific to males. Administration of ascorbic acid did not change in MV from the 30-minute to the 210-minute test on males or females. These results suggest that daily administration of crocetin may attenuate physical fatigue in men.

  Mar. 2009, Nutrition research (New York, N.Y.), 29(3) (3), 145 - 50, English, International magazine

  Scientific journal


• Central nervous system fatigue alters autonomic nerve activity.

  Masaaki Tanaka, Kei Mizuno, Seiki Tajima, Tetsuya Sasabe, Yasuyoshi Watanabe

  AIMS: Fatigue is a common symptom in modern society. In order to clarify the mechanisms underlying fatigue, we examined the association between central nervous system fatigue and autonomic nerve activity. MAIN METHODS: The study group consisted of 20 healthy subjects. They performed the 2-back test for 30 min to induce fatigue. Just before and after the fatigue-inducing session, they completed the advanced trail making test (ATMT) for 30 min as a fatigue-evaluating task session. In order to measure autonomic nerve activity, electrocardiograms were monitored continuously throughout the experiment. KEY FINDINGS: After the fatigue-inducing task session, impaired task performance was demonstrated based on the total trial number and error counts of the ATMT. During the task session, although task performance as measured using the accuracy and the mean reaction time of the 2-back test was almost unchanged, electrocardiographic R-R wave interval analyses showed a decreased high-frequency component power and an increasing trend in the low-frequency component power/high-frequency component power ratio. SIGNIFICANCE: Decreased vagal nerve activity and increased sympathetic nerve activity are associated with central nervous system fatigue.

  Feb. 2009, Life sciences, 84(7-8) (7-8), 235 - 9, English, International magazine

  Scientific journal


• PET and Macro- and Microautoradiographic Studies Combined with Immunohistochemistry for Monitoring Rat Intestinal Ulceration and Healing Processes

  Masanori Yamato, Yosky Kataoka, Hiroshi Mizuma, Yasuhiro Wada, Yasuyoshi Watanabe

  Feb. 2009, JOURNAL OF NUCLEAR MEDICINE, 50(2) (2), 266 - 273, English, International magazine

  [Refereed]

  Scientific journal


• Molecular imaging reveals unique degenerative changes in experimental glaucoma.

  Kazuyuki Imamura, Hirotaka Onoe, Masamitsu Shimazawa, Satoshi Nozaki, Yasuhiro Wada, Koichi Kato, Hideki Nakajima, Hiroshi Mizuma, Kayo Onoe, Takazumi Taniguchi, Masaaki Sasaoka, Hideaki Hara, Shigeru Tanaka, Makoto Araie, Yasuyoshi Watanabe

  Experimentally induced changes in the central visual pathway were studied by using positron emission tomography in monkeys with unilateral hypertension glaucoma. In 2-[18F]fluoro-2-deoxy-glucose studies, monocular visual stimulation of the affected eye yielded significantly reduced neural responses in the occipital visuocortical areas. The response reduction was limited to the visual cortex ipsilateral to the affected eye, indicating the unique vulnerability of ipsilateral visual cortex in experimental unilateral glaucoma. In addition, in [11C]PK11195 positron emission tomography and immunohistochemical studies, selective accumulation of activated microglia, a sign of neural degeneration, was found bilaterally in lateral geniculate nuclei. The present findings establish the usefulness of noninvasive molecular imaging for early diagnosis of glaucoma by providing a sharper surrogate end point for an early phase of glaucoma.

  Jan. 2009, Neuroreport, 20(2) (2), 139 - 44, English, International magazine

  Scientific journal


• 6. Investigation of canalicular efflux mechanisms of SC-62807, a major metabolite of celecoxib

  Chunyong Wu, Hiroyuki Kusuhara, Yuichi Sugiyama, Tadayuki Takashima, Misato Takashima-Hirano, Hisashi Doi, Masaaki Suzuki, Yasuyoshi Watanabe

  2009, Japanese Pharmacology and Therapeutics, 37(1) (1), S-37 - S42, English

  Scientific journal


• Positron emission tomography (PET) study for the evaluation of in vivo hepatobiliary transport using 15R-[11C]TIC-Me

  Tadayuki Takashima, Hiroko Nagata, Takahiro Nakae, Yoshinobu Hashizume, Hisashi Doi, Yasuhiro Wada, Yilong Cui, Masaaki Suzuki, Satoshi Kitamura, Kazuya Maeda, Hiroyuki Kusuhara, Yuichi Sugiyama, Yasuyoshi Watanabe

  2009, Japanese Pharmacology and Therapeutics, 37(1) (1), S-65 - S-69, Japanese

  Scientific journal


• FDG-MicroPET and diffusion-weighted MR image evaluation of early changes after radiofrequency ablation in implanted VX2 tumors in rabbits.

  Tomohiro Ohira, Tomohisa Okuma, Toshiyuki Matsuoka, Yasuhiro Wada, Kenji Nakamura, Yasuyoshi Watanabe, Yuichi Inoue

  The objective of this study was to evaluate the early changes after radiofrequency ablation (RFA) in VX2 rabbit tumors implanted into the back muscles by diffusion-weighted magnetic resonance (MR) imaging and (18)F-2-fluoro-2-deoxy-D-glucose positron emission tomography ((18)F-FDG PET). Percutaneous CT-guided RFA was conducted in seven rabbits with implanted VX2 tumors. VX2 tumors on the other side were untreated and served as the control. MR imaging was performed with a clinical 1.5-T instrument 2 days after RFA, and FDG-PET, using a high-resolution PET scanner for small animals, was obtained 3 days after the procedure. The mean apparent diffusion coefficient (ADC) values and radioactivity count of untreated and ablated tumors were calculated. Untreated VX2 tumors showed hyperintensity on T1-, T2-, and diffusion-weighted MR images, ring-enhanced on contrast-enhanced T1-weighted imaging, and ring-shaped FDG accumulation on FDG-PET. Ablated VX2 tumors showed slight hyperintensity on T1-, T2-, and diffusion-weighed images, slight enhancement on contrast-enhanced T1-weighted images, and low accumulation on FDG-PET. The ADC value of ablated VX2 tumors (1.52 +/- 0.24 x 10(-3) mm(2)/s) was significantly higher than that of untreated tumors (1.09 +/- 0.12 x 10(-3); p < 0.05). The tumor/muscle ratio of ablated tumors (0.5 +/- 0.3) was significantly lower than that of untreated tumors (11.6 +/- 3.2; p < 0.05). Histopathological examination confirmed the lack of viable tumor cells in the ablated lesions. The results indicate that both ADC value and FDG-PET are potentially useful markers for monitoring the early effects of RFA.

  Jan. 2009, Cardiovascular and interventional radiology, 32(1) (1), 114 - 20, English, International magazine

  Scientific journal


• Mental and physical fatigue-related biochemical alterations.

  Satoshi Nozaki, Masaaki Tanaka, Kei Mizuno, Suzuka Ataka, Hiroshi Mizuma, Tsuyoshi Tahara, Tomohiro Sugino, Tomoko Shirai, Asami Eguchi, Kaori Okuyama, Kaoru Yoshida, Yoshitaka Kajimoto, Hirohiko Kuratsune, Osami Kajimoto, Yasuyoshi Watanabe

  OBJECTIVE: To confirm fatigue-related biochemical alterations, we measured various parameters just before and after relaxation and fatigue-inducing mental or physical sessions. METHODS: Fifty-four healthy volunteers were randomized to perform relaxation and fatigue-inducing mental and physical sessions for 4 h in a double-blind, three-crossover design. Before and after each session, subjects were asked to rate their subjective sensations of fatigue, and blood, saliva, and urine samples were taken. RESULTS: After the fatigue-inducing mental and physical sessions, subjective scores of fatigue were increased. After the fatigue-inducing mental session, the vanillylmandelic acid level in urine was higher and plasma valine level was lower than after the relaxation session. In contrast, after the fatigue-inducing physical session, serum citric acid, triacylglycerol, free fatty acid, ketone bodies, total carnitine, acylcarnitine, uric acid, creatine kinase, aspartate aminotransferase, lactate dehydrogenase, cortisol, dehydroepiandrosterone, dehydroepiandrosterone sulfate, plasma branched-chain amino acids, transforming growth factor-beta1 and -beta2, white blood cell and neutrophil counts, saliva cortisol and amylase, and urine vanillylmandelic acid levels were higher and serum free carnitine and plasma total amino acids and alanine levels were lower than those after the relaxation session. CONCLUSION: Some mental or physical fatigue-related biochemical changes were determined. Various biochemical alterations reflecting homeostatic perturbation and its responses might be shown. We believe that our results contribute to clarifying the mechanism of fatigue, developing evaluation methods, and establishing a basis for treatment.

  Jan. 2009, Nutrition (Burbank, Los Angeles County, Calif.), 25(1) (1), 51 - 7, English, International magazine

  Scientific journal


• Stress and coping styles are associated with severe fatigue in medical students.

  Masaaki Tanaka, Sanae Fukuda, Kei Mizuno, Hirohiko Kuratsune, Yasuyoshi Watanabe

  Fatigue is a common complaint among medical students and researchers consider it to be related to poor academic outcomes. The authors' goal in the present study was to determine whether stress and coping strategies were associated with fatigue in medical students. The study group consisted of 73 second-year healthy students attending the Osaka City University Graduate School of Medicine. Participants completed a questionnaire about fatigue (Japanese version of Chalder Fatigue Scale), stress, stress coping (Japanese version of the Coping Inventory for Stressful Situations), overwork, and nocturnal sleeping hours. On univariate and multivariate logistic regression analyses adjusted for age and gender, stress was positively associated with fatigue. In addition, after adjustment for age, gender, and emotion- and task-oriented stress coping activities, avoidance-oriented stress coping activity was associated with fatigue. The results suggest that stress and the coping style are correlated with fatigue in medical students.

  2009, Behavioral medicine (Washington, D.C.), 35(3) (3), 87 - 92, English, International magazine

  Scientific journal


• Neural excitation generates new astrocytes in the cerebral cortex of adult rats

  Yasuhisa Tamura, Guanghua Jin, Yilong Cui, Yasuyoshi Watanabe, Yosky Kataoka

  2009, NEUROSCIENCE RESEARCH, 65, S157 - S157, English


• Identification of transporters involved in the hepatobiliary transport of PET probe, 15R- [¹¹C]TIC, change in its plasma and hepatic concentration by drug interaction in humans and its prediction from in vitro experiments

  Yuichi Sugiyama, Satoshi Kitamura, Kazuya Maeda, Hiroyuki Kusuhara, Tadayuki Takashima, Hiroko Nagata, Yoshinobu Hashizume, Hisashi Doi, Takanori Nakae, Yasuhiro Wada, Yilong Cui, Masaaki Suzuki, Yasuyoshi Watanabe

  2009, Japanese Pharmacology and Therapeutics, 37(SUPPL. 1) (SUPPL. 1)

  Scientific journal


• USE OF POSITRON EMISSION TOMOGRAPHY FOR ANALYSIS OF DRUG DISPOSITION IN VIVO (2):- MOLECULAR IMAGING OF GASTROINTESTINAL DRUG ABSORPTION PROCESS-

  Ou Hiroyuki, Doi Hisashi, Watanabe Yasuyoshi, Yamashita Shinji, Masaoka Yoshie, Kataoka Makoto, Sakuma Shinji, Takashima Tadayuki, Hashizume Yoshinobu, Wada Yasuhiro, Hayashinaka Emi, Cui Yilong

  The Japanese Society for the Study of Xenobiotics, 2009, Abstracts of Annual meeting of Japanese Society for the Study of Xenobiotics, 24(0) (0), 138 - 138, Japanese


• Reliability and validity of the Japanese version of the Chalder Fatigue Scale among youth in Japan.

  Masaaki Tanaka, Sanae Fukuda, Kei Mizuno, Kyoko Imai-Matsumura, Takako Jodoi, Junko Kawatani, Miyuki Takano, Teruhisa Miike, Akemi Tomoda, Yasuyoshi Watanabe

  In the present study, the reliability and construct validity of the Japanese version of the Chalder Fatigue Scale was evaluated as a measure of severity of fatigue among young students in Japan. A healthy group comprised 27 Grade 6 primary school students and 28 Grade 1 junior high school students. The severely fatigued group were hospital outpatients with childhood chronic fatigue syndrome (n = 21). Principal components analysis with varimax rotation identified 4 factors which accounted for 63.2% of the total variance, as in the original English version. Internal consistency (Cronbach coefficient alpha) was .73, and test-retest reliability measured using Spearman rank correlation coefficient was .55. Scale scores of the healthy subjects were lower than those of the patients with childhood chronic fatigue syndrome. The reliability (alpha) and construct validity of the Japanese version of the scale among healthy students in Japan were satisfactory for research studies among healthy school students.

  Dec. 2008, Psychological reports, 103(3) (3), 682 - 90, English, International magazine

  Scientific journal


• First Positron Emission Tomography (PET) Imaging of Glycoproteins and Glycodendrimers by Efficient Chemical Labeling with [Ga-68]-DOTA

  Katsunori Tanaka, Eric Richard Oktavianus Siwu, Kaori Minami, Koki Hasegawa, Yousuke Kanayama, Hiroshi Mizuma, Yasuhiro Wada, Yasuyoshi Watanabe, Koichi Fukase

  Nov. 2008, GLYCOBIOLOGY, 18(11) (11), 981 - 981, English

  [Refereed]


• Relationships between dietary habits and the prevalence of fatigue in medical students.

  Masaaki Tanaka, Kei Mizuno, Sanae Fukuda, Yoshihito Shigihara, Yasuyoshi Watanabe

  OBJECTIVE: Fatigue, which is a common complaint among medical students, is related to poor academic outcomes. Because impaired dietary habits, such as skipping breakfast and taking meals irregularly, are correlated with poor school performances, whether those dietary habits were associated with the prevalence of fatigue was determined in medical students. METHODS: The study group consisted of 127 healthy second-year medical students attending Osaka City University Graduate School of Medicine. They completed a questionnaire dealing with fatigue (Japanese version of the Chalder Fatigue Scale), lifestyle, and academic performance. RESULTS: On multivariate logistic regression analyses adjusted for age, gender, body mass index, and nocturnal sleeping hours, skipping breakfast (completely skipping breakfast everyday versus having breakfast everyday; odds ratio 7.81, 95% confidence interval 2.00-30.52, P = 0.003) and taking meals irregularly (completely irregular versus always regular; odds ratio 6.89, 95% confidence interval 1.20-39.55, P = 0.030) were positively correlated with the prevalence of fatigue. CONCLUSION: Skipping breakfast and taking meals irregularly are associated with the prevalence of fatigue in medical students.

  Oct. 2008, Nutrition (Burbank, Los Angeles County, Calif.), 24(10) (10), 985 - 9, English, International magazine

  Scientific journal


• The neural basis of academic achievement motivation.

  Kei Mizuno, Masaaki Tanaka, Akira Ishii, Hiroki C Tanabe, Hirotaka Onoe, Norihiro Sadato, Yasuyoshi Watanabe

  We have used functional magnetic resonance imaging to study the neural correlates of motivation, concentrating on the motivation to learn and gain monetary rewards. We compared the activation in the brain obtained during reported high states of motivation for learning, with the ones observed when the motivation was based on monetary reward. Our results show that motivation to learn correlates with bilateral activity in the putamen, and that the higher the reported motivation, as derived from a questionnaire that each subject filled prior to scanning, the greater the change in the BOLD signals within the putamen. Monetary motivation also activated the putamen bilaterally, though the intensity of activity was not related to the monetary reward. We conclude that the putamen is critical for motivation in different domains and the extent of activity of the putamen may be pivotal to the motivation that drives academic achievement and thus academic successes.

  Aug. 2008, NeuroImage, 42(1) (1), 369 - 78, English, International magazine

  Scientific journal


• 疲労と意欲の脳科学 動物モデルを用いた中枢神経疲労の分子・神経メカニズムの解析(Neural mechanism of central fatigue in the animal models)

  崔 翼龍, 片岡 洋祐, 渡辺 恭良

  日本神経化学会, Aug. 2008, 神経化学, 47(2-3) (2-3), 220 - 220, English


• Effects of (-) -epigallocatechin gallate in liver of an animal model of combined (physical and mental) fatigue.

  Masaaki Tanaka, Yoshitake Baba, Yosky Kataoka, Noriaki Kinbara, Yuko M Sagesaka, Takami Kakuda, Yasuyoshi Watanabe

  OBJECTIVE: Fatigue can be classified as physical and mental depending on the cause. However, in our daily lives, combined fatigue, which is the combination of physical and mental fatigue, is most often experienced. In this study, the effects of (-)-epigallocatechin gallate (EGCg) on combined fatigue were assessed. METHODS: To produce an animal model of combined fatigue, rats were kept in a cage filled with water to a height of 1.5 cm for 5 d. To evaluate the extent of fatigue, the rats swam with a load of steel rings that weighed approximately 8% of their body weight and were attached to their tails. RESULTS: Fatigued rats treated with EGCg (50 or 100 mg/kg intraperitoneally [not for 25 mg/kg]) for 5 d could swim longer than fatigued animals given saline. Although levels of thiobarbituric acid-reactive substances in the plasma, brain, and skeletal muscle were not different between control and fatigued rats, thiobarbituric acid-reactive substance levels were higher in livers of fatigued animals than in livers of control animals. Oral intake of EGCg (50 or 100 mg/kg) for 5 d significantly decreased thiobarbituric acid-reactive substance levels in livers of fatigued animals. CONCLUSION: These results suggest that EGCg (50 or 100 mg/kg) is effective for attenuating fatigue. EGCg given orally appears to have an antioxidant effect on the oxidatively damaged liver of fatigued animals.

  Jun. 2008, Nutrition (Burbank, Los Angeles County, Calif.), 24(6) (6), 599 - 603, English, International magazine

  Scientific journal


• Reduced energy utilization in the brain is a feature of an animal model of fatigue.

  Masaaki Tanaka, Yasuyoshi Watanabe

  Recently, the authors established an animal model of fatigue. The fatigued animals showed reduced 2-[18F]fluoro-2-deoxy-D-glucose uptake in their brain, although their blood glucose level did not differ from that of the control animals. For further clarification, the study measured regional cerebral blood flow, ATP level, and the ability of mitochondria to produce ATP in the brain of the fatigued and control rats. The fatigued animals showed almost equal regional cerebral blood flow, a significantly higher ATP level, and almost equal mitochondria ability to produce ATP. These data suggest that decreased energy utilization in the brain is a feature of fatigue.

  May 2008, The International journal of neuroscience, 118(5) (5), 683 - 92, English, International magazine

  Scientific journal


• Antifatigue effects of coenzyme Q10 during physical fatigue.

  Kei Mizuno, Masaaki Tanaka, Satoshi Nozaki, Hiroshi Mizuma, Suzuka Ataka, Tsuyoshi Tahara, Tomohiro Sugino, Tomoko Shirai, Yoshitaka Kajimoto, Hirohiko Kuratsune, Osami Kajimoto, Yasuyoshi Watanabe

  OBJECTIVE: This study examined the effects of coenzyme Q10 administration on physical fatigue. METHODS: In a double-blinded, placebo-controlled, three crossover design, 17 healthy volunteers were randomized to oral coenzyme Q10 (100 or 300 mg/d) or placebo administration for 8 d. As a fatigue-inducing physical task, subjects performed workload trials on a bicycle ergometer at fixed workloads twice for 2 h and then rested for 4 h. During the physical tasks, subjects performed non-workload trials with maximum velocity for 10 s at 30 min (30-min trial) after the start of physical tasks and 30 min before the end of the tasks (210-min trial). RESULTS: The change in maximum velocity from the 30- to the 210-min trial in the 300-mg coenzyme Q10-administered group was higher than that in the placebo group. In addition, subjective fatigue sensation measured on a visual analog scale in the 300-mg coenzyme Q10-administered group after the fatigue-inducing physical task and recovery period was alleviated when compared with that in the placebo group. CONCLUSION: Oral administration of coenzyme Q10 improved subjective fatigue sensation and physical performance during fatigue-inducing workload trials and might prevent unfavorable conditions as a result of physical fatigue.

  Apr. 2008, Nutrition (Burbank, Los Angeles County, Calif.), 24(4) (4), 293 - 9, English, International magazine

  Scientific journal


• Alteration in [11C]vorozole binding to aromatase in neuronal cells of rat brain induced by anabolic androgenic steroids and flutamide.

  Kayo Takahashi, Yasuhisa Tamura, Yasuyoshi Watanabe, Bengt Långström, Mats Bergström

  In a previous study, we demonstrated that androgenic-anabolic steroids increased aromatase expression in the bed nucleus of stria terminalis and preoptic area in rat brain, as evaluated using autoradiography with [11C]vorozole, a potential positron emission tomography tracer for aromatase. In this study, we explored whether the increase in aromatase binding is mediated via androgen receptors and whether this increase occurs in neurons or glial cells. Rats were given nandrolone decanoate (15 mg/kg body weight once every 3 days) and flutamide (20 mg/kg/day) alone or in combination for 20 days. Results indicated a significant increase of [11C]vorozole binding by nandrolone decanoate in the bed nucleus of the stria terminalis and preoptic area, as in our previous study. Flutamide treatment, on the other hand, decreased [11C]vorozole binding in the bed nucleus of the stria terminalis, preoptic area, and medial amygdala. Immunohistochemical examination demonstrated that upregulation of aromatase expression occurred in neurons. Our findings suggest that aromatase is regulated through an androgen receptor-mediated system. This aromatase-specific tracer and the positron emission tomography technique could be useful for exploring the role of aromatase in anabolic androgenic steroids abusers.

  Mar. 2008, Neuroreport, 19(4) (4), 431 - 5, English, International magazine

  Scientific journal


• CBEX-Dr配合飲料の健常者における抗疲労効果

  田中 雅彰, 鴫原 良仁, 藤井 比佐子, 平山 佳伸, 渡辺 恭良

  ライフサイエンス出版(株), Mar. 2008, 薬理と治療, 36(3) (3), 199 - 212, Japanese


• Effects of oral administration of caffeine and D-ribose on mental fatigue.

  Suzuka Ataka, Masaaki Tanaka, Satoshi Nozaki, Hiroshi Mizuma, Kei Mizuno, Tsuyoshi Tahara, Tomohiro Sugino, Tomoko Shirai, Yoshitaka Kajimoto, Hirohiko Kuratsune, Osami Kajimoto, Yasuyoshi Watanabe

  OBJECTIVE: We examined the effects of administering two different candidate antifatigue substances, caffeine and D-ribose, on mental fatigue. METHODS: In a double-blinded, placebo-controlled, three-way crossover design, 17 healthy volunteers were randomized to oral caffeine (200 mg/d), D-ribose (2000 mg/d), or placebo for 8 d. As fatigue-inducing mental tasks, subjects performed a 30-min Uchida-Kraepelin psychodiagnostic test and a 30-min advanced trail-making test on four occasions. RESULTS: During the tasks, the task performance of the caffeine group was better than that of the placebo group. However, after the fatigue-inducing tasks, although subjective perception of fatigue, motivation, or sleepiness was not significantly different, plasma branched-chain amino acid levels in the caffeine group were lower than those of the placebo group. Administration of D-ribose had no effect. CONCLUSION: Because plasma branched-chain amino acid levels are decreased by mental fatigue, these results suggest that administration of caffeine improved task performance through the enhancement of central nervous system activity without increasing the sensation of fatigue. However, further decreases in branched-chain amino acid levels indicate that caffeine might promote deeper fatigue than placebo. Unfortunately, research subsequent to our study design has shown that D-ribose dosing higher than we used is needed to see a clinical effect and therefore no conclusions can be made from this study as to the efficacy of D-ribose.

  Mar. 2008, Nutrition (Burbank, Los Angeles County, Calif.), 24(3) (3), 233 - 8, English, International magazine

  Scientific journal


• A new amyloid beta variant favoring oligomerization in Alzheimer's-type dementia.

  Takami Tomiyama, Tetsu Nagata, Hiroyuki Shimada, Rie Teraoka, Akiko Fukushima, Hyoue Kanemitsu, Hiroshi Takuma, Ryozo Kuwano, Masaki Imagawa, Suzuka Ataka, Yasuhiro Wada, Eito Yoshioka, Tomoyuki Nishizaki, Yasuyoshi Watanabe, Hiroshi Mori

  OBJECTIVE: Soluble oligomers of amyloid beta (Abeta), rather than amyloid fibrils, have been proposed to initiate synaptic and cognitive dysfunction in Alzheimer's disease (AD). However, there is no direct evidence in humans that this mechanism can cause AD. Here, we report a novel amyloid precursor protein (APP) mutation that may provide evidence to address this question. METHODS: A Japanese pedigree showing Alzheimer's-type dementia was examined for mutations in APP, PSEN1, and PSEN2. In addition, 5,310 Japanese people, including 2,121 patients with AD, were screened for the novel APP mutation. The pathogenic effects of this mutation on Abeta production, degradation, aggregation, and synaptotoxicity were also investigated. RESULTS: We identified a novel APP mutation (E693Delta) producing variant Abeta lacking gulutamate-22 (E22Delta) in Japanese pedigrees showing Alzheimer's-type dementia and AD. Although the secretion of total Abeta was markedly reduced by this mutation, the variant Abeta was more resistant to proteolytic degradation. The mutant peptides showed the unique aggregation property of enhanced oligomerization but no fibrillization, and inhibited hippocampal long-term potentiation more potently than wild-type peptide in rats in vivo. Consistent with the nonfibrillogenic property of the variant Abeta, a very low amyloid signal was observed in the patient's brain on positron emission tomography using Pittsburgh compound-B. INTERPRETATION: The E693Delta mutation has been suggested as a cause of dementia because of enhanced formation of synaptotoxic Abeta oligomers. Our findings may provide genetic validation in humans for the emerging hypothesis that the synaptic and cognitive impairment in AD is primarily caused by soluble Abeta oligomers.

  Mar. 2008, Annals of neurology, 63(3) (3), 377 - 87, English, International magazine

  Scientific journal


• Up-regulated neuronal COX-2 expression after cortical spreading depression is involved in non-REM sleep induction in rats

  Yilong Cui, Yosky Kataoka, Takashi Inui, Takatoshi Mochizuki, Hirotaka Onoe, Kiyoshi Matsumura, Yoshihiro Urade, Hisao Yamada, Yasuyoshi Watanabe

  4, Mar. 2008, Journal of Neuroscience Research, 86(4) (4), 929 - 936, English, International magazine

  [Refereed]

  Scientific journal


• A method for the synthesis of an oseltamivir PET tracer.

  Masataka Morita, Toshihiko Sone, Kenzo Yamatsugu, Yoshihiro Sohtome, Shigeki Matsunaga, Motomu Kanai, Yasuyoshi Watanabe, Masakatsu Shibasaki

  A protocol applicable for the synthesis of an oseltamivir positron emission tomography (PET) tracer was developed. Acetylation of amine 3 with CH(3)COCl, followed by deprotection and aqueous workup, produced oseltamivir 4 from 3 within 10 min. The obtained 4 was sufficiently pure for PET studies. This method can be extended to PET tracer synthesis using CH(3)(11)COCl.

  Jan. 2008, Bioorganic & medicinal chemistry letters, 18(2) (2), 600 - 2, English, International magazine

  Scientific journal


• Development and validation of a new fatigue scale for fatigued subjects with and without chronic fatigue syndrome

  Sanae Fukuda, Shoko Takashima, Masao Iwase, Kouzi Yamaguti, Hirohiko Kuratsune, Yasuyoshi Watanabe

  Springer Japan, 2008, Fatigue Science for Human Health, 89 - 102, English

  [Refereed]

  In book


• A submicrogram-scale protocol for biomolecule-based PET imaging by rapid 6pi-azaelectrocyclization: visualization of sialic acid dependent circulatory residence of glycoproteins.

  Katsunori Tanaka, Tatsuro Masuyama, Koki Hasegawa, Tsuyoshi Tahara, Hiroshi Mizuma, Yasuhiro Wada, Yasuyoshi Watanabe, Koichi Fukase

  2008, Angewandte Chemie (International ed. in English), 47(1) (1), 102 - 5, English, International magazine

  Scientific journal


• Factors influencing the academic motivation of individual college students

  Masahiro Yoshida, Masaaki Tanaka, Kei Mizuno, Akira Ishii, Kumi Nozaki, Ayako Urakawa, Yuki Cho, Yosky Kataoka, Yasuyoshi Watanabe

  2008, INTERNATIONAL JOURNAL OF NEUROSCIENCE, 118(10) (10), 1400 - 1411, English, International magazine

  [Refereed]

  Scientific journal


• Morphological changes of cortical NG2+cells in cerebral neocortex of aged rats

  Yasuhisa Tamura, Mitsuyo Maeda, Kayo Takahashi, Yilong Cui, Yasuyoshi Watanabe, Yosky Kataoka

  2008, NEUROSCIENCE RESEARCH, 61, S158 - S158, English


• EVALUATION OF IN VIVO HEPATOBILIARY TRANSPORT USING POSITRON EMISSION TOMOGRAPHY (PET)

  Takashima Tadayuki, kusuhara Hiroyuki, Sugiyama Yuichi, Watanabe Yasuyoshi, Kitamura Satoshi, Nagata Hiroko, Doi Hisashi, Nakae Takahiro, Wada Yasuhiro, Cui Yilong, Suzuki Masaaki, Maeda Kazuya

  The Japanese Society for the Study of Xenobiotics, 2008, Abstracts of Annual meeting of Japanese Society for the Study of Xenobiotics, 23(0) (0), 76 - 76, Japanese


• Fatigue and sleep induction following excessive activation of the central nervous system

  Kataoka Yosky, Cui Yilong, Tamura Yasuhisa, Yamato Masanori, Jin Guanghua, Watanabe Yasuyoshi

  Two experimental animal models for central fatigue have been developed by excessive activation of the central nervous system of rats; induction of cortical spreading depression, the propagation of neuronal membrane depolarization throughout the cerebral cortex, and long-term intracranial self-stimulation. We have reported that prostaglandins including PGD₂, PGE₂, and PGF_2α were produced by COX-2 expression in neurons in the cerebral cortex following cortical spreading depression. In such a model for neuronal excitation in the cortex, the amount of non-REM sleep, but not of REM sleep, increased subsequently for several hours in the animals, and the increase was completely attenuated by application of NS-398, a COX-2 inhibitor. In a long-term intracranial self-stimulation study, resting behavior and non-REM sleep appeared a few hours after the start of stimulation, and such behavioral changes were also inhibited by application of an inhibitor of COX-2. These observations indicate that arachidonic acid cascade plays an important role in a common molecular and neural system in such animal models for fatigue following neuronal activation in the central nervous system, and relieves excessive brain activity by inducing resting behavior and non-REM sleep. [J Physiol Sci. 2008;58 Suppl:S18]

  PHYSIOLOGICAL SOCIETY OF JAPAN, 2008, Proceedings of Annual Meeting of the Physiological Society of Japan, 2008(0) (0), 18 - 18


• Tissue factor expression on monocytes induced by anti-phospholipid antibodies as a strong risk factor for thromboembolic complications in SLE patients.

  Nojima J, Masuda Y, Iwatani Y, Suehisa E, Futsukaichi Y, Kuratsune H, Watanabe Y, Takano T, Hidaka Y, Kanakura Y

  Our aim was to clarify the role of anti-phospholipid antibodies in the pathogenesis of monocyte tissue factor (TF) expression and thromboembolic complications (TE) in patients with SLE. We examined cell surface expression of TF on monocytes in 93 SLE patients. Monocyte TF expression was significantly higher in SLE patients who had TE than in other SLE patients, and confirmed that the high expression of monocyte TF was a strong risk factor for TE. Furthermore, the presence of anti-cardiolipin/beta2-glycoprotein I antibodies (anti-CL/beta2-GPI) was strongly associated with the high expression of monocyte TF. We therefore studied the in vitro effect of IgG anti-CL/beta2-GPI on lipopolysaccharide (LPS)-induced expression of TF on monocytes in healthy peripheral blood and found that purified IgG containing anti-CL/beta2-GPI significantly enhanced LPS-induced monocyte TF expression. These results suggest that anti-CL/beta2-GPI cause persistently high TF expression on monocyte, which may contribute to the risk of thromboembolic events in SLE patients.

  2008, Biochem Biophys Res Commun., 365(1) (1), 195 - 200, Japanese, International magazine

  [Refereed]

  Others


• Arteriosclerosis obliterans associated with anti- cardiolipin antibody/β2-glycoprotein I antibodies as a strong risk factor for ischaemic heart disease in patients with systemic lupus erythematosus.

  Nojima J, Masuda Y, Iwatani Y, Kuratsune H, Watanabe Y, Suehisa E, Takano T, Hidaka Y, Kanakura Y

  2008, Rheumatology, 47, 684 - 689, Japanese

  [Refereed]

  Scientific journal


• Effects of increased endogenous serotonin on the in vivo binding of [11C]DASB to serotonin transporters in conscious monkey brain.

  Shigeyuki Yamamoto, Hirotaka Onoe, Hideo Tsukada, Yasuyoshi Watanabe

  Using a combination of positron emission tomography (PET) and the microdialysis technique, the effects of increased endogenous serotonin (5-hydroxytryptamine; 5-HT) on the binding of [(11)C]DASB to 5-HT transporters (5-HTT) were investigated in the conscious monkey brain. Five rhesus monkeys (Macaca mulatta) were scanned with [(11)C]DASB under the control condition and the increased endogenous 5-HT condition, in which 5-hydroxy-L-tryptophan (5-HTP) was administered (20 mg/kg, i.v.) before the PET scan. Compared with the control scan, the 5-HTP administration significantly decreased the binding potential (BP) (BP = B(max)/K(d)) of [(11)C]DASB in several brain regions. The mean % decrease of BP was biggest in the caudate and putamen. Two monkeys were scanned with [(11)C]5-HTP to assess the amino acid decarboxylase (AADC) activity in the brain, resulting in the high activity in the caudate and putamen. Microdialysis measurements showed that although 5-HTP administration (20 mg/kg, i.v.) increased the extracellular 5-HT levels in both the prefrontal cortex and caudate, the increase of the 5-HT level in the caudate was 27 times higher than that in the prefrontal cortex. These results suggest that the caudate and putamen, both of which show high AADC activity, convert 5-HTP to 5-HT at a high rate, and the increased 5-HT competes with [(11)C]DASB for the 5-HTT.

  Sep. 2007, Synapse (New York, N.Y.), 61(9) (9), 724 - 31, English, International magazine

  Scientific journal


• Intracellular translocation of glutathione S-transferase pi during oligodendrocyte differentiation in adult rat cerebral cortex in vivo

  Y. Tamura, Y. Kataoka, Y. Cui, Y. Takamori, Y. Watanabe, H. Yamada

  Aug. 2007, NEUROSCIENCE, 148(2) (2), 535 - 540, English

  [Refereed]

  Scientific journal


• [Molecular/neural mechanisms of fatigue].

  Yasuyoshi Watanabe

  Jun. 2007, Nihon rinsho. Japanese journal of clinical medicine, 65(6) (6), 972 - 4, Japanese, Domestic magazine

  Scientific journal


• [Estimation of fatigue state in patient with CFS using actigraph and R-R interval power spectrum analysis].

  Seiki Tajima, Hirohiko Kuratsune, Kouzi Yamaguti, Ayumi Takahashi, Shoko Takashima, Yasuyoshi Watanabe, Yoshiki Nishizawa

  OBJECTIVES: In this study, we try to estimate the fatigue state using actigraphy and R-R interval power spectrum analysis. RESULTS: Actigraphy analysis showed that mean awake activity was decreased and duration of sleep was prolonged in patients with chronic fatigue syndrome (CFS), significantly (p < 0.001). Both of sleep episodes in wake period and wake episodes in sleep period were significantly increased in CFS patients in comparison with healthy volunteers (p < 0.001) In autonomic nerve analysis, sleep/awake ratio of high frequency component was significantly decreased in patients with CFS (p < 0.05). CONCLUSION: The quality of sleep in patients with CFS was decreased because of increase of wake episodes in sleep period. Also the lack of parasympathetic activation during sleep period might be associated with the deterioration of sleep quality in patients with CFS.

  Jun. 2007, Nihon rinsho. Japanese journal of clinical medicine, 65(6) (6), 1057 - 64, Japanese, Domestic magazine

  Scientific journal


• Multi-directional differentiation of doublecortin- and NG2-immunopositive progenitor cells in the adult rat neocortex in vivo

  Yasuhisa Tamura, Yosky Kataoka, Yilong Cui, Yasuharu Takamori, Yasuyoshi Watanabe, Hisao Yamada

  Jun. 2007, EUROPEAN JOURNAL OF NEUROSCIENCE, 25(12) (12), 3489 - 3498, English, International magazine

  [Refereed]

  Scientific journal


• Effects of Applephenon and ascorbic acid on physical fatigue.

  Suzuka Ataka, Masaaki Tanaka, Satoshi Nozaki, Hiroshi Mizuma, Kei Mizuno, Tsuyoshi Tahara, Tomohiro Sugino, Tomoko Shirai, Yoshitaka Kajimoto, Hirohiko Kuratsune, Osami Kajimoto, Yasuyoshi Watanabe

  OBJECTIVE: We examined the effects of Applephenon and ascorbic acid administration on physical fatigue. METHODS: In a double-blinded, placebo-controlled, three-way crossover design, 18 healthy volunteers were randomized to oral Applephenon (1200 mg/d), ascorbic acid (1000 mg/d), or placebo for 8 d. The fatigue-inducing physical task consisted of workload trials on a bicycle ergometer at fixed workloads for 2 h on two occasions. During the test, subjects performed non-workload trials with maximum velocity for 10 s at 30 min (30-min trial) after the start of the test and 30 min before the end of the test (210-min trial). RESULTS: The change in maximum velocity between the 30- and 210-min trials was higher in the group given Applephenon than in the group given placebo; ascorbic acid had no effect. CONCLUSION: These results suggest that Applephenon attenuates physical fatigue, whereas ascorbic acid does not.

  May 2007, Nutrition (Burbank, Los Angeles County, Calif.), 23(5) (5), 419 - 23, English, International magazine

  Scientific journal


• [Molecular imaging for drug development].

  Yasuyoshi Watanabe

  In vivo molecular imaging has become a key technology for drug development and pathophysiological science. We are mostly utilizing PET (positron emission tomography) as a first-choice modality, because of its ultra-high sensitivity for molecules, adequate temporal and spatial resolution, and especially broad spectrum of target molecules. The present status for development of PET molecular probes, instrumentations including microPET, and the methods for quantitative analyses will be introduced with some examples. In vivo molecular imaging could bring the high-quality information about: (1) Molecular diagnosis for living patients with symptoms (2) Closer approach for etiology and differential diagnosis (3) Direct follow-up of key molecules as disease markers (4) Pharmacokinetics/Pharmacodynamics in primates/human (5) Dose finding information for individuals, corresponding to SNP (6) Direct evidence for accumulation in non-target organs: Related to adverse effects (7) Drug effects with surrogate markers (8) Early decision of dropout substances (drug candidates). In 2005, RIKEN and National Institute of Radiological Science were selected as the key centers for development of All-Japan research network to further promote mutual international and multi-disciplinary collaboration on in vivo molecular imaging. On this occasion, the concept and project themes will also be introduced.

  Mar. 2007, Brain and nerve = Shinkei kenkyu no shinpo, 59(3) (3), 209 - 14, Japanese, Domestic magazine

  Scientific journal


• Decrease of hepatic delta-aminolevulinate dehydratase activity in an animal model of fatigue.

  Tsuyoshi Tahara, Masaaki Tanaka, Satoshi Nozaki, Guanghua Jin, Hirotaka Onoe, Yasuyoshi Watanabe

  Fatigue can be defined physiologically as inability to maintain the expected power output. At present, no standard of fatigue are yet available. In order to find biomarkers of fatigue, we investigated the level of delta-aminolevulinic acid (ALA), the first intermediate metabolite in the heme biosynthetic pathway, in the plasma and urine of an animal model of fatigue. To prepare fatigued animals, we kept rats for 5 days in a cage filled with water to a height of 1.5 cm. As a result, the plasma and urinary ALA levels were increased in the fatigued animals as compared with those in the control animals. One day after the rats had been returned to their normal cages, these increased levels were restored to the control ones. We also examined the activity of the enzyme ALA dehydratase (ALAD), which is the second enzyme in the heme biosynthetic pathway, and ALAD gene expression during the fatigue and its recovery sessions. The ALAD activity, as well as its gene expression, in the liver of the fatigued animals was decreased as compared with those of the control animals. Both activity and gene expression of ALAD were recovered to their respective control levels after the rats had been allowed to rest in their normal cages for 1 day. Furthermore, the activity of ALA synthase (ALAS), the rate-limiting enzyme in the heme biosynthesis, in the liver was increased after the fatigue session for 5 days. Although this level of increase in the plasma concentration of ALA may not induce fatigue, increase in plasma and urinary ALA levels can be biomarkers of fatigue.

  Feb. 2007, Biochemical and biophysical research communications, 353(4) (4), 1068 - 73, English, International magazine

  Scientific journal


• [Molecular/neural mechanisms of fatigue and the way to overcome fatigue].

  Yasuyoshi Watanabe

  Feb. 2007, Nihon yakurigaku zasshi. Folia pharmacologica Japonica, 129(2) (2), 94 - 8, Japanese, Domestic magazine

  Scientific journal


• [Molecular imaging for drug development].

  Yasuyoshi Watanabe

  In vivo molecular imaging has become a key technology for pathophysiological science and drug development. We are mostly utilizing PET(positron emission tomography) as a first-choice modality, because of its ultra-high sensitivity for molecules, adequate temporal and spatial resolution, and especially broad spectrum of target molecules. In vivo molecular imaging could bring the high-quality information about: 1. Molecular diagnosis for living patients with symptoms 2. Closer approach for etiology and differential diagnosis 3. Direct follow-up of key molecules as disease markers 4. Pharmacokinetics/Pharmacodynamics in primates/human 5. Dose finding information for individuals, corresponding to SNPs 6. Direct evidence for accumulation in non-target organs related to adverse effects 7. Drug effects with surrogate markers 8. Early decision of dropout substances (drug candidates) Here, the examples are shown as beta-amyloid imaging for Alzheimer's and mild cognitive impairment, serotonin transporter imaging for chronic fatigue, and dopaminergic components imaging for evaluation of drug for autistic spectrum disorder. In 2005, RIKEN and National Institute of Radiological Science were selected as the key centers for development of All-Japan research network to further promote mutual international and multi -disciplinary collaboration on in vivo molecular imaging.

  Feb. 2007, Nihon rinsho. Japanese journal of clinical medicine, 65(2) (2), 357 - 62, Japanese, Domestic magazine

  Scientific journal


• Increase in [11C]vorozole binding to aromatase in the hypothalamus in rats treated with anabolic androgenic steroids.

  Kayo Takahashi, Mathias Hallberg, Kristina Magnusson, Fred Nyberg, Yasuyoshi Watanabe, Bengt Långström, Mats Bergström

  In the present study, we investigated the alteration of aromatase expression in the brain by anabolic androgenic steroid treatment in male rats. The rats were given nandrolone decanoate (15 mg/kg/day) for 14 days, and the brains were used for autoradiography with [C]vorozole, which has been developed as a positron emission tomography tracer for aromatase by our group. The results indicated a significant increase of [C]vorozole binding by anabolic androgenic steroids in the bed nucleus of the stria terminalis and preoptic area. In contrast, no significant change of [C]vorozole binding was observed in the medial amygdala. Our results suggest that aromatase is significantly upregulated in the bed nucleus of the stria terminalis and preoptic area by anabolic androgenic steroids and also suggest that androgens regulate aromatase differently in these structures compared with the medial amygdala.

  Jan. 2007, Neuroreport, 18(2) (2), 171 - 4, English, International magazine

  Scientific journal


• Comparison of dynamic FDG-microPET study in a rabbit turpentine-induced inflammatory model and in a rabbit VX2 tumor model.

  Yoshimasa Hamazawa, Koichi Koyama, Terue Okamura, Yasuhiro Wada, Tomoko Wakasa, Tomohisa Okuma, Yasuyoshi Watanabe, Yuichi Inoue

  PURPOSE: We investigated the optimum time for the differentiation tumor from inflammation using dynamic FDG-microPET scans obtained by a MicroPET P4 scanner in animal models. MATERIALS AND METHODS: Forty-six rabbits with 92 inflammatory lesions that were induced 2, 5, 7, 14, 30 and 60 days after 0.2 ml (Group 1) or 1.0 ml (Group 2) of turpentine oil injection were used as inflammatory models. Five rabbits with 10 VX2 tumors were used as the tumor model. Helical CT scans were performed before the PET studies. In the PET study, after 4 hours fasting, and following transmission scans and dynamic emission data acquisitions were performed until 2 hours after intravenous FDG injection. Images were reconstructed every 10 minutes using a filtered-back projection method. PET images were analyzed visually referring to CT images. For quantitative analysis, the inflammation-to-muscle (I/M) ratio and tumor-to-muscle (T/M) ratio were calculated after regions of interest were set in tumors and muscles referring to CT images and the time-I/M ratio and time-T/M ratio curves (TRCs) were prepared to show the change over time in these ratios. The histological appearance of both inflammatory lesions and tumor lesions were examined and compared with the CT and FDG-microPET images. RESULTS: In visual and quantitative analysis, All the I/M ratios and the T/M ratios increased over time except that Day 60 of Group 1 showed an almost flat curve. The TRC of the T/M ratio showed a linear increasing curve over time, while that of the I/M ratios showed a parabolic increasing over time at the most. FDG uptake in the inflammatory lesions reflected the histological findings. For differentiating tumors from inflammatory lesions with the early image acquired at 40 min for dual-time imaging, the delayed image must be acquired 30 min after the early image, while imaging at 90 min or later after intravenous FDG injection was necessary in single-time-point imaging. CONCLUSION: Our results suggest the possibility of shortening the overall testing time in clinical practice by adopting dual-time-point imaging rather than single-time-point imaging.

  Jan. 2007, Annals of nuclear medicine, 21(1) (1), 47 - 55, English, Domestic magazine

  Scientific journal


• Spectroscopic diagnosis of anti-phospholipid antibodies by visible and near-infrared spectroscopy in SLE patients’ plasma samples.

  Nojima J, Sakudo A, Hakariya Y, Kuratsune H, Watanabe Y, Kanakura Y, Ikuta K

  The purpose of this study was to investigate whether visible and near-infrared (Vis-NIR) spectroscopy can be used for diagnoses of anti-phospholipid syndrome (APS). Vis-NIR spectra from 90 plasma samples [anti-phospholipid antibodies (aPLs)-positive group, n=48; aPLs-negative group, n=42] were subjected to principal component analysis (PCA) and soft independent modeling of class analogy (SIMCA) to develop multivariate models to discriminate between aPLs-positive and aPLs-negative. Both PCA and SIMCA models were further assessed by the prediction of 84 masked other determinations. The PCA model predicted successful discrimination of the masked samples with respect to aPLs-positive and aPLs-negative. The SIMCA model predicted 42 of 48 (87.5%) aPLs-positive patients and 33 of 36 (91.7%) aPLs-negative patients of Vis-NIR spectra from masked samples correctly. These results suggest that Vis-NIR spectroscopy combined with multivariate analysis could provide a promising tool to objectively diagnose APS.

  2007, Biochem Biophys Res Commun., 362(2) (2), 522 - 524, Japanese, International magazine

  [Refereed]

  Scientific journal


• Neuroprotection by a central nervous system-type prostacyclin receptor ligand demonstrated in monkeys subjected to middle cerebral artery occlusion and reperfusion - A positron emission tomography study

  Yilong Cui, Hiroyuki Takamatsu, Takeharu Kakiuchi, Hiroyuki Ohba, Yosky Kataoka, Chihiro Yokoyama, Hirotaka Onoe, Yumiko Watanabe, Takamitsu Hosoya, Masaaki Suzuki, Ryoji Noyori, Hideo Tsukada, Yasuyoshi Watanabe

  Nov. 2006, STROKE, 37(11) (11), 2830 - 2836, English, International magazine

  [Refereed]

  Scientific journal


• 18F-FDG small-animal PET for monitoring the therapeutic effect of CT-guided radiofrequency ablation on implanted VX2 lung tumors in rabbits.

  Tomohisa Okuma, Toshiyuki Matsuoka, Terue Okamura, Yasuhiro Wada, Akira Yamamoto, Yoshimasa Oyama, Koichi Koyama, Kenji Nakamura, Yasuyoshi Watanabe, Yuichi Inoue

  UNLABELLED: The primary goals of this study were to investigate the behavior of normal lung tissues after radiofrequency ablation (RFA) and to determine the suitability of 18F-FDG PET, using a dedicated small-animal scanner, for monitoring the early therapeutic effects of RFA on VX2 lung tumors (VX2s) in rabbits. METHODS: Fourteen Japanese white rabbits with normal lungs underwent RFA, followed by 18F-FDG PET at 1 d and at 1, 2, 4, and 8 wk. In addition, 7 rabbits with untreated VX2s underwent 18F-FDG PET, and 13 rabbits with RFA-treated VX2s underwent 18F-FDG PET at 1 d (n = 7) or 1 wk (n = 6) after the treatment. RESULTS: After RFA of normal lungs, ring-shaped accumulations of 18F-FDG, which coincided with inflammation caused by ablation, were observed. The mean early- (40-60 min after injection) and delayed (100-120 min)-phase ablated lesion-to-muscle ratios were, respectively, 2.9 +/- 1.0 and 3.3 +/- 0.8 (1 d), 4.1 +/- 0.6 and 5.2 +/- 0.9 (1 wk), 4.1 +/- 1.0 and 5.3 +/- 1.5 (2 wk), 3.1 +/- 0.5 and 3.6 +/- 1.1 (4 wk), and 1.8 +/- 0.1 and 2.3 +/- 0.1 (8 wk). At 4 and 8 wk, the uptake was less than that at 1 and 2 wk (P < 0.05). VX2s showed mean tumor-to-muscle ratios of 6.6 +/- 2.1 and 8.6 +/- 3.3 at the early and delayed phases, respectively. For ablated tumors, the respective ratios were 0.8 +/- 0.4 and 1.1 +/- 0.7 (1 d) and 1.2 +/- 0.5 and 1.5 +/- 0.7 (1 wk). These values were significantly lower than those for nonablated tumors (P < 0.001). Histopathologic examination confirmed the absence of viable tumors. 18F-FDG accumulation around ablated tumors reflected thermally damaged normal tissues and was significantly lower than that of control VX2s (P < 0.01). CONCLUSION: Our data suggest that 18F-FDG PET is promising for evaluating the therapeutic response of lung malignancies to RFA: Accumulation of 18F-FDG in surrounding normal tissues appears to be time dependent, and the data suggest that, clinically, 18F-FDG PET should be performed 4 wk or more after RFA. Delayed-phase images seem to better distinguish tumor from inflammation than do early-phase images.

  Aug. 2006, Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 47(8) (8), 1351 - 8, English, International magazine

  Scientific journal


• Spectroscopic diagnosis of chronic fatigue syndrome by visible and near-infrared spectroscopy in serum samples.

  Akikazu Sakudo, Hirohiko Kuratsune, Takanori Kobayashi, Seiki Tajima, Yasuyoshi Watanabe, Kazuyoshi Ikuta

  To investigate visible and near-infrared (Vis-NIR) spectroscopy enabling chronic fatigue syndrome (CFS) diagnosis, we subjected sera from CFS patients as well as healthy donors to Vis-NIR spectroscopy. Vis-NIR spectra in the 600-1100 nm region for sera from 77 CFS patients and 71 healthy donors were subjected to principal component analysis (PCA) and soft independent modeling of class analogy (SIMCA) to develop multivariate models to discriminate between CFS patients and healthy donors. The model was further assessed by the prediction of 99 masked other determinations (54 in the healthy group and 45 in the CFS patient group). The PCA model predicted successful discrimination of the masked samples. The SIMCA model predicted 54 of 54 (100%) healthy donors and 42 of 45 (93.3%) CFS patients of Vis-NIR spectra from masked serum samples correctly. These results suggest that Vis-NIR spectroscopy for sera combined with chemometrics analysis could provide a promising tool to objectively diagnose CFS.

  Jul. 2006, Biochemical and biophysical research communications, 345(4) (4), 1513 - 6, English, International magazine

  Scientific journal


• Imaging of aromatase distribution in rat and rhesus monkey brains with [11C]vorozole.

  Kayo Takahashi, Mats Bergström, Pernilla Frändberg, Eva-Lotta Vesström, Yasuyoshi Watanabe, Bengt Långström

  Aromatase is an enzyme that converts androgens to estrogens and may play a role in mood and mental status. The aim of this study was to demonstrate that brain aromatase distribution could be evaluated with a novel positron emission tomography (PET) tracer [(11)C]vorozole. Vorozole is a nonsteroidal aromatase inhibitor that reversibly binds to the heme domain of aromatase. In vitro experiments in rat brain, using frozen section autoradiography, illustrated specific binding in the medial amygdala (MA), the bed nucleus of stria terminalis (BST) and the preoptic area (POA) of male rat brain. Specific binding in female rat brain was found in the MA and the BST; however, the signals were lower than those of males. The K(d) of [(11)C]vorozole binding to aromatase in MA was determined to be 0.60+/-0.06 nM by Scatchard plot analysis using homogenates. An in vivo PET study in female rhesus monkey brain demonstrated the uptake of [(11)C]vorozole in the amygdala, where the uptake was blocked by the presence of excess amounts of unlabeled vorozole. Thus, this tracer has a high affinity for brain aromatase and could have a potential for in vivo aromatase imaging. This technique might enable the investigation of human brain aromatase in healthy and diseased persons.

  Jul. 2006, Nuclear medicine and biology, 33(5) (5), 599 - 605, English, International magazine

  Scientific journal


• Preservation of functional architecture in visual cortex of cats with experimentally induced hydrocephalus

  K Imamura, S Tanaka, J Ribot, M Kobayashi, M Yamamoto, K Nakadate, Y Watanabe

  Apr. 2006, EUROPEAN JOURNAL OF NEUROSCIENCE, 23(8) (8), 2087 - 2098, English, International magazine

  [Refereed]

  Scientific journal


• Development of real-time bioradiographic system for functional and metabolic imaging in living brain tissue.

  Toru Sasaki, Akinori Iwamoto, Hisashi Tsuboi, Yasuyoshi Watanabe

  We have developed a novel imaging system "real-time bioradiography", which is able to estimate the dynamic changes of physiological function and metabolism in living tissues using positron emitter-labeled tracers and chemiluminescence probes. The apparatus is comprised of a photon-counting camera, image-controller, culturing chamber, reflexible solid scintillator and temperature-controlled imaging chamber. The image distribution of radioactivity and chemiluminescence was acquirable with the reflexible solid scintillator and without, respectively. The reflexible solid scintillator is effective to exclude the affect of intra-objective different light reflectivity on radiation detection and to improve the efficiency of radiation detection. To test and to demonstrate the efficacy of this system, we examined the glucose metabolism and superoxide formation during hypoxia-reoxygenation in living brain tissues using 2-[18F]fluoro-2-deoxy-D-glucose (FDG) and Lucigenin, respectively. FDG uptake and chemiluminescence images were obtained at time frames of every 15 min. Glucose metabolism was enhanced during the hypoxic treatment, but the superoxide formation was enhanced during reoxygenation. The enhanced glucose metabolism during hypoxia might cause the increase in superoxide formation during reoxygenation. Thus, this new method would open up possibilities to approach simultaneous biological monitoring of a variety of biochemical events with various combinations of positron emitter-labeled tracers and chemiluminescence probes in living tissues.

  Mar. 2006, Brain research, 1077(1) (1), 161 - 9, English, International magazine

  Scientific journal


• Administration of secretin for autism alters dopamine metabolism in the central nervous system.

  Yoshihiro Toda, Kenji Mori, Toshiaki Hashimoto, Masahito Miyazaki, Satoshi Nozaki, Yasuyoshi Watanabe, Yasuhiro Kuroda, Shoji Kagami

  We evaluated the clinical effects of intravenously administered secretin in 12 children with autism (age range: 4-6 years, median age: 9 years, boy:girl=8:4). In addition, we investigated the association between improvement in symptoms and changes in the cerebrospinal fluid (CSF) homovanillic acid (HVA),5-hydroxyindole-3-acetic acid (5-HIAA), and 6R-5,6,7,8-tetrahydro-L-biopterin (BH(4)) levels after administration. After administration of secretin, the Autism Diagnostic Interview-Revised (ADI-R) score improved in 7 of the 12 children. However, the score deteriorated in 2 of the 12 children (in the item of 'restricted and repetitive, stereotyped interests and behaviors'). The HVA and BH(4) levels in CSF were increased in all children with improvement in the ADI-R score. In contrast, no patient without the elevation of the BH(4) level showed improvement in the score. These findings suggest that secretin activated metabolic turnover of dopamine in the central nervous system via BH(4), improving symptoms.

  Mar. 2006, Brain & development, 28(2) (2), 99 - 103, English, International magazine

  Scientific journal


• Reduced responsiveness is an essential feature of chronic fatigue syndrome: a fMRI study.

  Masaaki Tanaka, Norihiro Sadato, Tomohisa Okada, Kei Mizuno, Tetsuya Sasabe, Hiroki C Tanabe, Daisuke N Saito, Hirotaka Onoe, Hirohiko Kuratsune, Yasuyoshi Watanabe

  BACKGROUND: Although the neural mechanism of chronic fatigue syndrome has been investigated by a number of researchers, it remains poorly understood. METHODS: Using functional magnetic resonance imaging, we studied brain responsiveness in 6 male chronic fatigue syndrome patients and in 7 age-matched male healthy volunteers. Responsiveness of auditory cortices to transient, short-lived, noise reduction was measured while subjects performed a fatigue-inducing continual visual search task. RESULTS: Responsiveness of the task-dependent brain regions was decreased after the fatigue-inducing task in the normal and chronic fatigue syndrome subjects and the decrement of the responsiveness was equivalent between the 2 groups. In contrast, during the fatigue-inducing period, although responsiveness of auditory cortices remained constant in the normal subjects, it was attenuated in the chronic fatigue syndrome patients. In addition, the rate of this attenuation was positively correlated with the subjective sensation of fatigue as measured using a fatigue visual analogue scale, immediately before the magnetic resonance imaging session. CONCLUSION: Chronic fatigue syndrome may be characterised by attenuation of the responsiveness to stimuli not directly related to the fatigue-inducing task.

  Feb. 2006, BMC neurology, 6, 9 - 9, English, International magazine

  Scientific journal


• Usefulness of FDG-microPET for early evaluation of therapeutic effects on VX2 rabbit carcinoma.

  Kentaro Ishii, Masako N Hosono, Yasuhiro Wada, Mitsuyo Maeda, Satoko Kondo, Yoshie Takada, Takuhito Tada, Terue Okamura, Yasuyoshi Watanabe, Yuichi Inoue

  PURPOSE: The aim of this study was to determine the potential use of high-resolution FDG-microPET for predicting the primary effects of radiotherapy and/or hyperthermia on tumor-bearing rabbits. METHODS: Twenty-eight VX2 xenografts in the thighs of rabbits were divided into the following 5 treatment groups: radiotherapy at a single dose of 10, 20 or 30 Gy, hyperthermia (43 degrees Celsius, 1 hour), and the combination of radiotherapy and hyperthermia (10 Gy + 43 degrees Celsius, 1 hour). FDG-microPET images were obtained by using a microPET P4 system at pretreatment and at 24 hours and 7 days after treatment. For the evaluation by FDG-microPET, tumor/muscle (T/M) ratios, retention index [RI = (T/M ratio at 120 min - T/M ratio at 60 min) / T/M ratio at 60 min], and time activity curve (TAC) were acquired. RESULTS: We divided the xenografts into a responder group (partial response + stable disease, n=14) and a non-responder group (progressive disease, n = 14). The T/M ratio at 24 hours after the treatment in the responder group was decreased remarkably with that at pre-treatment (p < 0.05), while in the non-responder group it showed no significant change between the time points. The RI and TAC patterns were comparable to T/M ratios in each treatment group. T/M ratios, RI, and TAC indicated marked changes at the time point of 24 hours in the responder group, although the tumors did not show any significant hange in volume at that time. Photomicrographs of sections showed that the number of viable tumor cells in the responder group decreased at 24 hours after treatment and that inflammatory cell infiltration was marked and almost all viable tumor cells had disappeared by day 7 after treatment. CONCLUSION: These results suggest that early evaluation by FDG-microPET, especially 24 hours after treatment, is useful to predict the primary effects of the treatment. Histological analysis showed that inflammatory cell infiltration at 7 days after treatment was considered to be a cause of accumulation of FDG in the tumors that showed a significant decrease in tumor cell number. This false-positive should be noted when predicting tumor response by FDG accumulation.

  Feb. 2006, Annals of nuclear medicine, 20(2) (2), 123 - 30, English, Domestic magazine

  Scientific journal


• Brain-derived neurotrophic factor enhances expression of superior cervical ganglia clone 10 in lateral geniculate nucleus and visual cortex of developing kittens

  K Imamura, H Morii, K Nakadate, T Yamada, N Mataga, Y Watanabe, N Mori

  Feb. 2006, EUROPEAN JOURNAL OF NEUROSCIENCE, 23(3) (3), 637 - 648, English, International magazine

  [Refereed]

  Scientific journal


• Two subtypes of NG2(+) cells in the perineuronal territory of the adult rat neocortex

  Yasuhisa Tamura, Yosky Kataoka, Yilong Cui, Yasuharu Takamori, Yasuyoshi Watanabe, Hisao Yamada

  2006, NEUROSCIENCE RESEARCH, 55, S146 - S146, English


• Cellular and subcellular localization of alpha-1 adrenoceptors in the rat visual cortex

  K. Nakadate, K. Imamura, Y. Watanabe

  2006, Neuroscience, 141(4) (4), 1783 - 1792, English

  [Refereed]

  Scientific journal


• Altered expression of neprilysin family members in the pituitary gland of sleep-disturbed rats, an animal model of severe fatigue.

  Tokiko Ogawa, Sumiko Kiryu-Seo, Masaaki Tanaka, Hiroyuki Konishi, Nobuhisa Iwata, Takaomi Saido, Yasuyoshi Watanabe, Hiroshi Kiyama

  Alterations of the expression of some peptidases in the pituitary gland of a fatigued rat model were identified. Rats were kept in a cage filled with water to a height of 1.5 cm to disturb deep sleep. After 24-h sleep disturbance, expression of neutral endopeptidase 24.11 (neprilysin) mRNA was increased in the intermediate lobe of the pituitary gland, whereas the mRNA expression of another family member, damage-induced neuronal endopeptidase, which is normally expressed in a subgroup of anterior pituitary cells, was significantly suppressed. These alterations were demonstrated by RT-PCR, northern blotting and in situ hybridization. Other family members, such as neprilysin 2 and endothelin converting enzyme-1, did not show any change in mRNA expression. An increase of neprilysin mRNA expression was not seen in any other tissues of the sleep-disturbed rats. The enzymatic activity of neprilysin was also increased in the pituitary. The augmentation of neprilysin expression and activity was prolonged as long as the sleep disturbance continued (up to 5 days), and returned to the basal level when rats were allowed to sleep freely. These results suggest that peptide processing and degradation in the pituitary may be an influential factor in fatigued states such as sleep disturbance.

  Nov. 2005, Journal of neurochemistry, 95(4) (4), 1156 - 66, English, International magazine

  Scientific journal


• Tetrahydrobiopterin in the treatment of children with autistic disorder: a double-blind placebo-controlled crossover study.

  Torsten Danfors, Anne-Liis von Knorring, Per Hartvig, Bengt Langstrom, Robert Moulder, Bo Stromberg, Richard Torstenson, Ulrika Wester, Yasuyoshi Watanabe, Orvar Eeg-Olofsson

  Twelve children, all boys, aged 4 to 7 years, with a diagnosis of autistic disorder and low concentrations of spinal 6R-l-erythro-5,6,7,8-tetrahydrobiopterin (tetrahydrobiopterin) were selected to participate in a double-blind, randomized, placebo-controlled, crossover study. The children received a daily dose of 3 mg tetrahydrobiopterin per kilogram during 6 months alternating with placebo. Treatment-induced effects were assessed with the Childhood Autism Rating Scale every third month. The results showed small nonsignificant changes in the total scores of Childhood Autism Rating Scale after 3- and 6-month treatment. Post hoc analysis looking at the 3 core symptoms of autism, that is, social interaction, communication, and stereotyped behaviors, revealed a significant improvement of the social interaction score after 6 months of active treatment. In addition, a high positive correlation was found between response of the social interaction score and IQ. The results indicate a possible effect of tetrahydrobiopterin treatment.

  Oct. 2005, Journal of clinical psychopharmacology, 25(5) (5), 485 - 9, English, International magazine

  Scientific journal


• A dynamic shift of neural network activity before and after learning-set formation.

  Chihiro Yokoyama, Hideo Tsukada, Yasuyoshi Watanabe, Hirotaka Onoe

  Learning-set (LS) is a property of insight and hypothesis testing characterized by the ability to solve novel problems based on previous experiences with problem solving. However, the neural organization and mechanisms underlying LS remain unclear. To further characterize this process, positron emission tomography (PET) studies with [15O]H2O were performed to measure regional cerebral blood flow (rCBF) during the learning phase of the two-choice visual discrimination task under the LS paradigm in rhesus monkeys. When comparing studies before and after LS formation, the orbitofrontal and lateral prefrontal cortices were differentially activated, and functional connections between these structures and the striatum, which contributes to habit learning, were altered. We conclude that changes in the lateral prefrontal cortex during problem solving may contribute to the executive function of working memory and also inhibit control of a primitive learning system, thereby promoting LS formation.

  Jun. 2005, Cerebral cortex (New York, N.Y. : 1991), 15(6) (6), 796 - 801, English, International magazine

  Scientific journal


• MicroPET detection of enhanced 18F-FDG utilization by PKA inhibitor in awake rat brain.

  Rie Hosoi, Akira Matsumura, Shigekazu Mizokawa, Masaaki Tanaka, Fusao Nakamura, Kaoru Kobayashi, Yasuyoshi Watanabe, Osamu Inoue

  To obtain PET imaging of glucose metabolism in the brains of conscious rats, a method of rat head fixation was developed. PET measurement with microPET was performed for 60 min after 18F-FDG injection. Significant enhancement of glucose utilization in the right striatum was observed with infusion of Rp-adenosine-3,5-cyclic phosphorothioate triethylamine (Rp-cAMPS). FDG uptake increments were also seen in the ipsilateral frontal cortex and thalamus. As initial FDG uptake in the brain was not significantly altered by Rp-cAMPS, increased glucose metabolism might be due to an increase in the phosphorylation rate by hexokinase rather than the delivery process from plasma to the brain. In contrast to awake rats, the effect of Rp-cAMPS was abolished by anesthesia using chloral hydrate, indicating that neuronal activity has an important role in short term regulation of hexokinase activity through the cAMP/PKA system in the brain. These results strongly demonstrated the value of measuring glucose utilization in the brains of conscious rats.

  Mar. 2005, Brain research, 1039(1-2) (1-2), 199 - 202, English, International magazine

  Scientific journal


• Directed differentiation of telencephalic precursors from embryonic stem cells.

  Kiichi Watanabe, Daisuke Kamiya, Ayaka Nishiyama, Tomoko Katayama, Satoshi Nozaki, Hiroshi Kawasaki, Yasuyoshi Watanabe, Kenji Mizuseki, Yoshiki Sasai

  We demonstrate directed differentiation of telencephalic precursors from mouse embryonic stem (ES) cells using optimized serum-free suspension culture (SFEB culture). Treatment with Wnt and Nodal antagonists (Dkk1 and LeftyA) during the first 5 d of SFEB culture causes nearly selective neural differentiation in ES cells ( approximately 90%). In the presence of Dkk1, with or without LeftyA, SFEB induces efficient generation ( approximately 35%) of cells expressing telencephalic marker Bf1. Wnt3a treatment during the late culture period increases the pallial telencephalic population (Pax6(+) cells yield up to 75% of Bf1(+) cells), whereas Shh promotes basal telencephalic differentiation (into Nkx2.1(+) and/or Islet1/2(+) cells) at the cost of pallial telencephalic differentiation. Thus, in the absence of caudalizing signals, floating aggregates of ES cells generate naive telencephalic precursors that acquire subregional identities by responding to extracellular patterning signals.

  Mar. 2005, Nature neuroscience, 8(3) (3), 288 - 96, English, International magazine

  Scientific journal


• Prevention and/or recovery effects by green odor(s) on fatigue and green-odor-responsible brain regions as revealed by PET.

  Yasuyoshi Watanabe, Tetsuya Sasabe, Kouzi Yamaguti, Masayuki Kobayashi, Shigeyuki Yamamoto, Hirohiko Kuratsune, Kouta Sano, Akikazu Hatanaka, Hideo Tsukada, Hirotaka Onoe

  Jan. 2005, Chemical senses, 30 Suppl 1, i268-9, English, International magazine

  Scientific journal


• Reduction of serotonin transporters of patients with chronic fatigue syndrome.

  Shigeyuki Yamamoto, Yasuomi Ouchi, Hirotaka Onoe, Etsuji Yoshikawa, Hideo Tsukada, Hidetoshi Takahashi, Masao Iwase, Kouzi Yamaguti, Hirohiko Kuratsune, Yasuyoshi Watanabe

  To assess the involvement of serotonin in the symptoms of chronic fatigue syndrome, we investigated the serotonergic neurotransmitter system of chronic fatigue syndrome patients by the positron emission tomography (PET). Here we show that the density of serotonin transporters (5-HTTs) in the brain, as determined by using a radiotracer, [C](+)McN5652, was significantly reduced in the rostral subdivision of the anterior cingulate as compared with that in normal volunteers. This subdivision is different from that in the dorsal anterior cingulate in which binding potential values of individual patient showed a weak negative correlation with self-reported pain score of the patients. Therefore, an alteration of serotonergic system in the rostral anterior cingulate plays a key role in pathophysiology of chronic fatigue syndrome.

  Dec. 2004, Neuroreport, 15(17) (17), 2571 - 4, English, International magazine

  Scientific journal


• Functional imaging of gustatory perception and imagery: "top-down" processing of gustatory signals.

  Masayuki Kobayashi, Masaki Takeda, Noriaki Hattori, Masaki Fukunaga, Tetsuya Sasabe, Noriko Inoue, Yasuo Nagai, Tohru Sawada, Norihiro Sadato, Yasuyoshi Watanabe

  By recalling gustatory memories, it is possible to generate vivid gustatory perceptions in the absence of gustatory inputs. This gustatory image influences our gustatory processing. However, the mechanism of the "top-down" modulation of gustatory perception in the human is still unclear. Our findings propose a new perspective on the neural basis of gustatory processing. Although gustatory imagery and gustatory perception shared common parts of neural substrates, there was an asymmetrical topography of activation in the insula: the left insula was predominantly activated by gustatory imagery tasks. In addition, the middle and superior frontal gyri were not activated by gustatory perception but they participated in the generation of gustatory hallucinations. These regions in the frontal cortex may mediate the "top-down" control of retrieving gustatory information from the storage of long-term memories.

  Dec. 2004, NeuroImage, 23(4) (4), 1271 - 82, English, International magazine

  Scientific journal


• Mechanisms underlying fatigue: a voxel-based morphometric study of chronic fatigue syndrome.

  Tomohisa Okada, Masaaki Tanaka, Hirohiko Kuratsune, Yasuyoshi Watanabe, Norihiro Sadato

  BACKGROUND: Fatigue is a crucial sensation that triggers rest, yet its underlying neuronal mechanisms remain unclear. Intense long-term fatigue is a symptom of chronic fatigue syndrome, which is used as a model to study the mechanisms underlying fatigue. METHODS: Using magnetic resonance imaging, we conducted voxel-based morphometry of 16 patients and 49 age-matched healthy control subjects. RESULTS: We found that patients with chronic fatigue syndrome had reduced gray-matter volume in the bilateral prefrontal cortex. Within these areas, the volume reduction in the right prefrontal cortex paralleled the severity of the fatigue of the subjects. CONCLUSION: These results are consistent with previous reports of an abnormal distribution of acetyl-L-carnitine uptake, which is one of the biochemical markers of chronic fatigue syndrome, in the prefrontal cortex. Thus, the prefrontal cortex might be an important element of the neural system that regulates sensations of fatigue.

  Oct. 2004, BMC neurology, 4(1) (1), 14 - 14, English, International magazine

  Scientific journal


• Performance evaluation of microPET P4 for rat, rabbit and monkey

  Yasuhiro Wada, Akira Matsumura, Fusao Nakamura, Masaaki Tanaka, Hiroshi Mizuma, Kei Mizuno, Satoshi Nozaki, Hideki Nakajima, Satoko Kondo, Kentaro Ishii, Koichi Koyama, Yoshimasa Hamazawa, Tomohisa Okuma, Terue Okamura, Yuichi Inoue, Yasuyoshi Watanabe

  Aug. 2004, International Congress Series, 1265(C) (C), 69 - 73, English

  [Refereed]

  Scientific journal


• [Designed molecular probes in brain research: molecular imaging of IP2 receptor in the human brain].

  Masaaki Suzuki, Hisashi Doi, Koichi Kato, Takamitsu Hosoya, Yumiko Watanabe, Yasuyoshi Watanabe

  The study of the role of prostaglandins in living human brain requires a highly designed non-invasive molecular probe with a specific function in the central nervous system and high stability in an in vivo system in addition to the ability of blood-brain-barrier penetration. We succeeded in designing 15R-TIC, which binds with a novel prostacyclin receptor subtype (IP2) expressed specifically in the central nervous system. 15R-TIC exhibited a distinct nerve-protecting effect in both high oxygen and in vivo ischemic conditions. In addition, a rapid C-methylation reaction, developed in order to incorporate a short-lived 11C-positron nuclide into the molecule, realized the synthesis of 15R-[11C]TIC methyl ester with the radioactivity of 2.5 GBq. The molecular imaging was established for both monkey and human brains by intravenous injection of this positron emission tomography (PET) probe.

  Aug. 2004, Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology, 24(4) (4), 221 - 9, Japanese, Domestic magazine

  Scientific journal


• 脳内セロトニン神経系は片頭痛病態(Spreading depression)に影響する(Brain serotonergic nervous system modulates spreading depression: A pathophysiology of migraine)

  崔 翼龍, 片岡 洋祐, 田村 泰久, 李 慶華, 野崎 聡, 水間 広, 渡辺 恭良, 山田 久夫

  日本神経化学会, Aug. 2004, 神経化学, 43(2-3) (2-3), 358 - 358, English


• Increase in reaction time for solving problems during learning-set formation.

  Chihiro Yokoyama, Hirotaka Onoe, Yasuyoshi Watanabe

  Six rhesus monkeys were tested for a change in reaction time for problem-solving during a learning-set task, in which they showed progressive improvement in the rate of learning successive problems of visual discrimination. To evaluate the processing time for cognitive processes in problem-solving, the differences in release latency and movement time between the visual discrimination task and the visuomotor control task were defined. In their first experience, the monkeys required several hundreds of trials for solving the problem, and the Deltarelease latency was constant throughout the learning. With increasing experience, they solved problems within fewer trials than with the first problem. At this stage, the Deltarelease latency was high at the beginning and then decreased. The rise in the Deltarelease latency within the learning acquisition period increased depending on the amount of experience with problems they had solved, whereas the Deltamovement time within that period was not significantly affected by the experience with problems. The present findings suggest that the number of problem-solving experiences could promote profound cognitive processing, which may be related to a conceptual representation that actualizes the flexibility of learning, namely, the learning set.

  Jul. 2004, Behavioural brain research, 152(2) (2), 221 - 9, English, International magazine

  Scientific journal


• Use of FDG-microPET for detection of small nodules in a rabbit model of pulmonary metastatic cancer.

  Satoko Kondo, Masako N Hosono, Yasuhiro Wada, Kentaro Ishii, Akira Matsumura, Yoshie Takada, Mari Tashiro, Terue Okamura, Haruyuki Fukuda, Ryusaku Yamada, Yasuyoshi Watanabe, Yuichi Inoue

  OBJECTIVE: The performance of microPET using 18F-FDG was evaluated in a rabbit model of hematogenous pulmonary metastatic cancer. METHODS: A total of 15 Japanese white rabbits and VX-2 carcinoma were used in this study. In the microPET study, tumor-bearing rabbits were administered intravenously 74 MBq of 18F-FDG, and 30 min later, the emission data were acquired for 60 min. The transmission scans were performed with a 68Ge/68Ga external point source. To augment the anatomical information, we performed multi-detector row computed tomography (MDCT) in the combination with MDCT and microPET on 10 rabbits. The other 5 rabbits were followed once a week for 5 weeks only by microPET. Tumor/muscle (T/M) ratios were used for quantitative evaluation in this study. RESULTS: Multiple pulmonary nodules were detected by MDCT and microPET starting 14 days after the tumor injection. The high-uptake lesions in the lung detected by microPET corresponded well to the tumors detected by MDCT. The smallest nodule detected by microPET was ca. 1.5 mm in diameter. Overall, 87 nodules were detected by MDCT and the ratios of lesions detected by microPET to those by MDCT were 35.3%, 77.5%, and 90% for tumors equal to or smaller than 2 mm, 2-4 mm, and 4-6 mm in diameter, respectively. The respective T/M ratios were 2.41 +/- 0.41, 2.93 +/- 0.55, and 3.34 +/- 0.71. The T/M ratio increased with tumor size, but it was similar in each tumor size category. In the 35-day follow-up protocol, it was possible to follow sequentially the same tumor by the microPET. CONCLUSIONS: By FDG-microPET, it is possible to evaluate tumors larger than 2 mm in diameter and to follow the growth of individual tumors. Our results also suggest that the rabbit model of VX-2 pulmonary metastasis is a stable experimental model for evaluation using FDG. Monitoring of the therapeutic effects of anticancer drugs and radiation therapy could be tried by using this model and microPET.

  Feb. 2004, Annals of nuclear medicine, 18(1) (1), 51 - 7, English, Domestic magazine

  Scientific journal


• Inhibition period of self-stimulation and the involvement of the serotonergic nervous system in long-term intracranial self-stimulation in rats

  Cui Yilong, Kataoka Yosky, Li Qing-Hua, Nozaki Satoshi, Mizuma Hiroshi, Watanabe Yasuyoshi, Yamada Hisao

  Inhibition periods (less than 10 times/min) for dozens of minutes were often observed in a long-term (24 hours) intracranial self-stimulation (ICSS; 50-60 times/min) in rats; electrical stimulations were applied to the hemi-lateral medial forebrain bundle of rats when the rats pressed a lever. The inhibition was not induced by thermal effect on neural function or by muscular fatigue, since the animals in the inhibition period started ICSS again when more intensive stimulations to the ipsi-lateral medial forebrain bundle or stimulations to the contra-lateral medial forebrain bundle were applied to the animals. In such a long-term ICSS, the inhibition period was significantly decreased in the animals pharmacologically treated with 5,7-dihydroxy-tryptamine just after their birth for inducing degeneration of serotonergic neurons in the dorsal raphe nucleus, although the treatment did not affect ICSS in short duration. These observations indicate that the serotonergic nervous system facilitates or modulates the inhibition of the long-term ICSS and would be involved in weariness or fatigue sensation. [Jpn J Physiol 54 Suppl:S209 (2004)]

  PHYSIOLOGICAL SOCIETY OF JAPAN, 2004, Proceedings of Annual Meeting of the Physiological Society of Japan, 2004, S209 - S209


• Role of lactate in the brain energy metabolism: revealed by Bioradiography.

  Masaaki Tanaka, Fusao Nakamura, Shigekazu Mizokawa, Akira Matsumura, Kiyoshi Matsumura, Tetsuhito Murata, Makoto Shigematsu, Katsuhiro Kageyama, Hironobu Ochi, Yasuyoshi Watanabe

  To elucidate the role of lactate in the brain, we used a novel method, 'Bioradiography', in which the dynamic process could be followed in living slices by use of positron-emitter-labeled compounds and imaging plates. We studied the incorporation of 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) into rat brain slices incubated in oxygenated Krebs-Ringer solution. Under the glucose-free condition, [18F]FDG uptake rate in the cerebral cortex decreased with time and plateaued within 350 min but the addition of 5 mM lactate made the [18F]FDG uptake linear. When an inhibitor of the lactate transporter, 0.5 mM alpha-cyano-4-hydroxycinnamate (4-CIN) was applied to the glucose-free solution, the uptake rate decreased. Under the normal glucose condition, [18F]FDG uptake linearly increased for 6 h, but when 10 mM lactate was applied, the uptake rate decreased. In contrast, when 0.5 mM 4-CIN was applied to the normal glucose solution, [18F]FDG uptake rate increased. These results suggest that exogenous and endogenous lactate can substitute for glucose in the brain.

  Jan. 2004, Neuroscience research, 48(1) (1), 13 - 20, English, International magazine

  Scientific journal


• Unique expression patterns of 5-HT2A and 5-HT2C receptors in the rat brain during postnatal development: Western blot and immunohistochemical analyses

  QH Li, K Nakadate, S Tanaka-Nakadate, D Nakatsuka, YL Cui, Y Watanabe

  Jan. 2004, JOURNAL OF COMPARATIVE NEUROLOGY, 469(1) (1), 128 - 140, English, International magazine

  [Refereed]

  Scientific journal


• Recovery from fatigue: changes in local brain 2-[18F]fluoro-2-deoxy-D-glucose utilization measured by autoradiography and in brain monoamine levels of rat.

  Shigekazu Mizokawa, Masaaki Tanaka, Akira Matsumura, Satoshi Nozaki, Yasuyoshi Watanabe

  We recently established an animal model of fatigue in which rats were kept in a cage filled with water to a height of 1.5 cm for 5 days. In this way, after the fatigue session, they were returned to their home cage. Rats resting for 15 min or 2 h showed reduced 2-[18F]fluoro-2-deoxy-D-glucose uptake in their brain. Rats resting for 1 h showed a significantly increased ratio of 5-hydroxyindoleacetic acid/5-hydroxytryptamine, an index of serotonin turnover, in the frontal cortex, hippocampus, and cerebellum, and the ratio of [3,4-dihydroxyphenylacetic acid+homovanillic acid]/dopamine, an index of dopamine turnover, tended to be increased as compared with the control. These data suggest that improvement of glucose uptake and increased serotonergic and dopaminergic neuronal activities are associated with recovery from central fatigue.

  Dec. 2003, Neuroscience letters, 353(3) (3), 169 - 72, English, International magazine

  Scientific journal


• Establishment and assessment of a rat model of fatigue.

  Masaaki Tanaka, Fusao Nakamura, Shigekazu Mizokawa, Akira Matsumura, Satoshi Nozaki, Yasuyoshi Watanabe

  To establish an animal model of fatigue, we kept rats in a cage filled with water to a height of 1.5 cm. We selected a weight-loaded forced swimming test for evaluation of the extent of fatigue. Animals kept in the wet cage for 5 days showed a reduction in 2-[18F]fluoro-2-deoxy-D-glucose uptake into their brain. The session for 1 day showed significantly increased 5-hydroxyindoleacetic acid (5-HIAA)/5-hydroxytryptamine (5-HT) and [3,4-dihydroxyphenyl-acetic acid (DOPAC)+homovanillic acid (HVA)]/dopamine (DA) ratios in all brain regions, but the session for 5 days showed the restoration of the 5-HIAA/5-HT ratio in the hippocampus and hypothalamus and in the (DOPAC+HVA)/DA ratio in the striatum and hypothalamus. Our data suggest that decreased glucose uptake and insufficient serotonin and dopamine turnover introduced by deprivation of rest were correlated with central fatigue.

  Dec. 2003, Neuroscience letters, 352(3) (3), 159 - 62, English, International magazine

  Scientific journal


• Assessment of microPET performance in analyzing the rat brain under different types of anesthesia: comparison between quantitative data obtained with microPET and ex vivo autoradiography.

  Akira Matsumura, Shigekazu Mizokawa, Masaaki Tanaka, Yasuhiro Wada, Satoshi Nozaki, Fusao Nakamura, Susumu Shiomi, Hironobu Ochi, Yasuyoshi Watanabe

  MicroPET (positron emission tomography) has been implemented for use in experiments with small animals. However, the quantification and optimal conditions for scanning are not established yet. The aim of this study was to compare the results obtained by microPET with those by ex vivo autoradiography of rat brain slices, based on the 2-[18F]fluoro-2-deoxy-D-glucose (FDG) method, and to establish the optimal conditions for scanning. As an example, we examined glucose metabolism in the rat brain under 6 types of anesthesia and in the conscious state. The scanning conditions for the rat brain were (1) use of a 4-mm-thick leaden jacket, (2) an energy window of 350-650 keV, and (3) a coincidence time window of 6 ns. Under these conditions, the quantitative ROI data from microPET showed a good correlation with the corresponding ROI data from FDG autoradiography in the animal study (r2=0.81). With our protocol, when anesthesia was started 40 min after the FDG injection, the glucose metabolism was almost the same as that in the conscious rat brain.

  Dec. 2003, NeuroImage, 20(4) (4), 2040 - 50, English, International magazine

  Scientific journal


• Association between serotonin transporter gene polymorphism and chronic fatigue syndrome.

  Masaaki Narita, Naoko Nishigami, Naoko Narita, Kouzi Yamaguti, Nobuo Okado, Yasuyoshi Watanabe, Hirohiko Kuratsune

  Interaction between the hypothalamo-pituitary-adrenal axis and the serotonergic system is thought to be disrupted in chronic fatigue syndrome (CFS) patients. We examined a serotonin transporter (5-HTT) gene promoter polymorphism, which affects the transcriptional efficiency of 5-HTT, in 78 CFS patients using PCR amplification of the blood genomic DNA. A significant increase of longer (L and XL) alleic variants was found in the CFS patients compared to the controls both by the genotype-wise and the allele-wise analyses (both p<0.05, by chi(2) test and Fisher's exact test). Attenuated concentration of extracellular serotonin due to longer variants may cause higher susceptibility to CFS.

  Nov. 2003, Biochemical and biophysical research communications, 311(2) (2), 264 - 6, English, International magazine

  Scientific journal


• Diagnostic evaluation of 2', 5'-oligoadenylate synthetase activities and antibodies against Epstein-Barr virus and Coxiella burnetii in patients with chronic fatigue syndrome in Japan.

  Kazufumi Ikuta, Takeshi Yamada, Tokio Shimomura, Hirohiko Kuratsune, Ryuzo Kawahara, Shiro Ikawa, Eiko Ohnishi, Yoshihiro Sokawa, Hideto Fukushi, Katsuya Hirai, Yasuyoshi Watanabe, Takeshi Kurata, Teruo Kitani, Takeshi Sairenji

  To investigate the association of viral infections with chronic fatigue syndrome (CFS), we assayed 2', 5'-oligoadenylate synthetase (2-5AS) activities in peripheral blood mononuclear cells from CFS patients in Japan. These patients were diagnosed in two hospitals, H1 and H2, located in different areas of the country. The activities were detected in 19 (86%) and 7 (32%) of each of the 22 patients in H1 and H2, respectively, while they were detected in only four (11%) out of the 38 healthy controls. IFN-alpha was similarly detected in a few CFS patients and healthy controls. We also assayed the antibody titers against Epstein-Barr virus (EBV) and Coxiella burnetii in these patients. The EBV anti-EA-IgG antibodies were detected in two (9%) and seven (32%) of each of the 22 patients in H1 and H2, respectively. Anti-C. burnetii IgG antibodies were detected in six (27%) out of 22 patients in H1 but not in 22 patients in H2, while they were detected in one (11%) of the nine healthy controls. Some CFS patients may be associated with EBV or C. burnetii infection. There were some statistical correlations between the 2-5AS activities and antibody titers of EA-IgG (P < 0.05, Student's t-test) but not to the antibody titers of C. burnetii. The up-regulation of 2-5AS activities suggests immunological dysfunctions with some virus infections in the CFS patients. Our results indicate that 2-5AS activities are useful for a diagnostic marker of CFS and for exploring the complicated pathogenesis of CFS.

  Oct. 2003, Microbes and infection, 5(12) (12), 1096 - 102, English, International magazine

  Scientific journal


• Activation of the anterior cingulate gyrus by 'Green Odor': a positron emission tomography study in the monkey.

  Tetsuya Sasabe, Masayuki Kobayashi, Yusuke Kondo, Hirotaka Onoe, So Matsubara, Shigeyuki Yamamoto, Hideo Tsukada, Kayo Onoe, Hiroshi Watabe, Hidehiro Iida, Mikihiko Kogo, Kohta Sano, Akikazu Hatanaka, Tohru Sawada, Yasuyoshi Watanabe

  The equivalent mixture of cis-3-hexenol and trans-2-hexenal (hexenol/hexenal), 'green odor', is known to have a healing effect on the psychological damage caused by stress. Behavioral studies in humans and monkeys have revealed that hexenol/hexenal prevents the prolongation of reaction time caused by fatigue. In the present study, we investigated which brain regions are activated by the odor of hexenol/hexenal using positron emission tomography with alert monkeys. Regional cerebral blood flow (rCBF) in the prepyriform area (the primary olfactory cortex) was commonly increased by the passive application of odor: acetic acid, isoamylacetate or hexenol/hexenal. We observed rCBF increases in the orbitofrontal cortex (the secondary olfactory cortex) by these olfactory stimuli in two of three monkeys, and found no predominance of laterality of the activated hemisphere. Furthermore, rCBF increase in the cerebellum was observed in two of three monkeys, and the odor of acetic acid increased rCBF in the substantia innominata in all monkeys. In addition to these olfactory related regions, the anterior cingulate gyrus was activated by the odor of hexenol/hexenal. These findings suggest that the increase of rCBF in the anterior cingulate gyrus by the odor of hexenol/hexenal may contribute the healing effects of this mixture observed in the monkey.

  Sep. 2003, Chemical senses, 28(7) (7), 565 - 72, English, International magazine

  Scientific journal


• Role of acetyl-L-carnitine in the brain: revealed by Bioradiography.

  Masaaki Tanaka, Fusao Nakamura, Shigekazu Mizokawa, Akira Matsumura, Kiyoshi Matsumura, Yasuyoshi Watanabe

  To elucidate the role of acetyl-L-carnitine in the brain, we used a novel method, 'Bioradiography,' in which the dynamic process could be followed in living slices by use of positron-emitter labeled compounds and imaging plates. We studied the incorporation of 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) into rat brain slices incubated in oxygenated Krebs-Ringer solution. Under the glucose-free condition, [18F]FDG uptake rate decreased with time and plateaued within 350 min in the cerebral cortex and cerebellum, and the addition of 1 or 5mM acetyl-L-carnitine did not alter the [18F]FDG uptake rate. When a glutaminase inhibitor, 0.5mM 6-diazo-5-oxo-L-norleucine (DON), was added under the normal glucose condition, [18F]FDG uptake rate decreased. Acetyl-L-carnitine (1mM), which decreased [18F]FDG uptake rate, reversed this DON-induced decrease in [18F]FDG uptake rate in the cerebral cortex. These results suggest that acetyl-L-carnitine can be used for the production of releasable glutamate rather than as an energy source in the brain.

  Jul. 2003, Biochemical and biophysical research communications, 306(4) (4), 1064 - 9, English, International magazine

  Scientific journal


• Role of heme oxygenase-1 protein in the neuroprotective effects of cyclopentenone prostaglandin derivatives under oxidative stress.

  Takumi Satoh, Megumi Baba, Daisaku Nakatsuka, Yasuyuki Ishikawa, Hiroyuki Aburatani, Kyoji Furuta, Toshihisa Ishikawa, Hiroshi Hatanaka, Masaaki Suzuki, Yasuyoshi Watanabe

  Previously we found that some cyclopenteone prostaglandin derivatives (PGs), referred to as neurite outgrowth-promoting PGs (NEPPs), have dual biological activities of promoting neurite outgrowth and preventing neuronal death [Satoh et al. (2000) J. Neurochem., 75, 1092-1102; Satoh et al. (2001) J. Neurochem., 77, 50-62; Satoh et al. (2002) In Kikuchi, II. (ed.), Strategenic Medical Science Against Brain Attack. Springer-Verlag, Tokyo, pp. 78-93]. To investigate possible cellular mechanisms of the neuroprotective effects, we performed oligo hybridization-based DNA array analysis with mRNA isolated from HT22, a cell line that originated from a mouse hippocampal neuron. Several transcripts up-regulated by NEPP11 were identified. Because heme oxygenase 1 (HO-1) mRNA was the most prominently induced and was earlier reported to protect neuronal and non-neuronal cells against oxidative stress, we focused on it as a possible candidate responsible for the neuroprotective effects. We found NEPP11 to induce HO-1 protein (32 kDa) in HT22 cells in both the presence and the absence of glutamate, whereas non-neuroprotective prostaglandins (PGs) Delta12-PGJ2 or PGA2 did not. Overexpression of HO-1-green fluorescence protein (GFP) fusion protein significantly protected HT22 cells against oxidative glutamate toxicity, whereas that of GFP alone did not. Furthermore, biliverdin and bilirubin, products of HO-1 enzymatic activity on heme, protected HT22 cells from oxidative glutamate toxicity. These results, together with our previous results, suggest that NEPP11 activates the expression of HO-1 and that HO-1 produces biliverdin and bilirubin, which result in the inhibition of neuronal death induced by oxidative stress. NEPP11 is the first molecular probe reported to have a neuroprotective action through induction of HO-1 in neuronal cells.

  Jun. 2003, The European journal of neuroscience, 17(11) (11), 2249 - 55, English, International magazine

  Scientific journal


• [Neural and molecular mechanisms of fatigue and recovery from fatigue].

  Yasuyoshi Watanabe

  Fatigue is an indispensable biosignal for maintaining life. However, the neural/molecular mechanisms of fatigue are still unclear. Here, the recent progress in this field is introduced, mostly through our project research under the control of the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japanese Government. The sensing mechanisms of fatigue in the brain might be related to the orbitofrontal-dorsoprefrontal-cingulate triangle circuits. We hypothesized the neural circuits for fatigue sensation through our PET study on chronic fatigue patients and healthy volunteers. The serotonergic system might be involved in the sensation in the prefrontal cortex, although the hyperserotonin hypothesis might be wrong. The fatigue sensation is somehow related to hypofunction of the glutamatergic system through reduced uptake of acetyl-carnitine in the discrete brain regions. For creation of new methods and drugs overcoming fatigue, different types of animal models of fatigue were developed. By using such animal models, the green leaf odor, ascorbic acid, acetyl-carnitine, and tetrahydrobiopterin have been found to be effective.

  Jun. 2003, Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology, 23(3) (3), 149 - 53, Japanese, Domestic magazine

  Scientific journal


• Improvement by repeated administration of 6R-tetrahydrobiopterin of 5,7-dihydroxytryptamine-induced abnormal behaviors in immature rats.

  Hiroshi Mizuma, Mika Mizutani, Satoshi Nozaki, Hirohito Iizuka, Hideo Tohyama, Nobuhiro Nishimura, Yasuyoshi Watanabe, Ryuichiro Kohashi

  To clarify the therapeutic effects of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (6R-BH(4)) on the abnormal behaviors induced by neonatal 5,7-dihydroxytryptamine (5,7-DHT, 100 microg; i.c.v.) treatment in immature rats, 6R-BH(4) (10-40 mg/kg) was administered intraperitoneally from 22nd to 28th days or only once on the 28th day. The locomotion activities decreased dramatically in 5,7-DHT-treated rats (p<0.01; as compared to controls) on the 28th day. The reduced locomotion was recovered dose-dependently by repeated administration of 6R-BH(4), whereas it was not altered after a single injection of 6R-BH(4). In addition, repeated administration of 6R-BH(4) significantly facilitated 5-HT turnover ratio (5-HIAA/5-HT) in the striatum, cerebral cortex, and cerebellum. These findings suggest that the behavioral restoration by 6R-BH(4) might be due to the enhancement of 5-HT turnover by accumulated but not a single dose of 6R-BH(4).

  Feb. 2003, Biochemical and biophysical research communications, 302(1) (1), 156 - 61, English, International magazine

  Scientific journal


• [Non-human primate behaviors as models for development of higher cognitive functions].

  Chihiro Yokoyama, Hirotaka Onoe, Kayo Onoe, Hideo Tsukada, Yasuyoshi Watanabe, Kenji Fukui

  Non-human primate behaviors have a special value for the neurobiological study of the development of higher cognitive functions of humans, because of the near evolutional relation between two species. We surveyed results and futures of neurobiological studies of a retrieval task, a learning-set and a self-injurious behavior expressed by non-human primates. On the retrieval task that is related to the development of inhibitory control, it was revealed a hierarchical ordering of inhibitory control processes in which the distinct neuronal circuits were involved. On the learning-set that is related to the development of abstract thinking, neural circuits for the individual learning dramatically changed from an automatic process to a cognitive process depending on the learning-set formation. The self-injurious behavior is expressed during early normal development in humans, and no other animals but non-human primates express it without administration of drugs. For that behavior, probable change in interactions of multiple monoaminergic systems was suggested as its underlying causes. Further studies on development of higher cognitive functions using non-human primates could be required for understanding the nature of human cognition.

  Feb. 2003, Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology, 23(1) (1), 1 - 9, Japanese, Domestic magazine

  Scientific journal


• Targeted tissue oxidation in the cerebral cortex induces local prolonged depolarization and cortical spreading depression in the rat brain

  Y Cui, Y Kataoka, QH Li, C Yokoyama, A Yamagata, N Mochizuki-Oda, J Watanabe, H Yamada, Y Watanabe

  Jan. 2003, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 300(3) (3), 631 - 636, English, International magazine

  [Refereed]

  Scientific journal


• Attenuated fever in pregnant rats is associated with blunted syntheses of brain cyclooxygenase-2 and PGE2.

  Kyoko Imai-Matsumura, Kiyoshi Matsumura, Akira Terao, Yasuyoshi Watanabe

  Attenuation of fever occurs in pregnant animals. This study examined a hypothesis that brain production of PGE(2), the final mediator of fever, is suppressed in pregnant animals. Near-term pregnant rats and age-matched nonpregnant female rats were injected with lipopolysaccharide (100 microg/kg) intraperitoneally. Four hours later, colonic temperature was measured, their cerebrospinal fluid (CSF) was sampled for PGE(2) assay, and their brains were processed for immunohistochemistry of cyclooxygenase-2, an enzyme involved in PGE(2) biosynthesis. In the pregnant rats, lipopolysaccharide injection resulted in significantly smaller elevations in both colonic temperature and CSF-PGE(2) level than in nonpregnant rats. In the pregnant rats, lipopolysaccharide-induced cyclooxygenase-2 expression was blunted in terms of the number of positive cells. There was a significant correlation between PGE(2) level in CSF and the number of cyclooxygenase-2-positive endothelial cells. These results suggest that suppressed PGE(2) production in the brain is one cause for the attenuated fever response at near-term pregnancy and that this suppressed PGE(2) production is due to the suppressed induction of cyclooxygenase-2 in brain endothelial cells.

  Dec. 2002, American journal of physiology. Regulatory, integrative and comparative physiology, 283(6) (6), R1346-53, English, International magazine

  Scientific journal


• [Cyclopentenone prostaglandin derivatives as neuroprotective compounds].

  Takumi Satoh, Yasuyoshi Watanabe

  Dec. 2002, Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme, 47(15) (15), 2032 - 6, Japanese, Domestic magazine

  Scientific journal


• Neuropilin-2 is overexpressed in the rat brain after limbic seizures.

  Shuichi Shimakawa, Shuhei Suzuki, Ryohei Miyamoto, Kimitaka Takitani, Katsuji Tanaka, Takuya Tanabe, Eiji Wakamiya, Fusao Nakamura, Miyuki Kuno, Shushi Matsuura, Yasuyoshi Watanabe, Hiroshi Tamai

  Structural rearrangement and synaptic reorganization are known to occur in the brain after seizures. If neuronal rearrangement after seizures always results in abnormal hyperexcitability, it would provide an accurate pathway to the appropriate target and as a result, it may be the mechanism of epileptogenesis. This study examined the mechanism of axon guidance in the mature rat brain after seizures by evaluating the expression of the axonal guidance molecule, neuropilin-2. We assessed the expression of neuropilin-2 by northern blotting and immunohistochemistry in rat with seizures created by kindling stimulation and kainate injection.The neuropilin-2 mRNA level was increased in the whole brain of the rats at 24 h after either type of seizure. Neuropilin-2 mRNA was not increased at 2 weeks after the last stimulation. Immunohistochemistry demonstrated that neuropilin-2 protein was increased in the dentate gyrus and the entorhinal cortex in the both seizure models. These findings suggested that there was overexpression of neuropilin-2 in the brains of mature rats with different types of seizure. Accordingly, neuropilin-2 might regulate remodeling after seizures as it does during the development of the hippocampal formation. Our findings suggest that axons may not project and outgrow 'aberrantly' after seizures, but may be regulated by the chemorepellent effect through neuropilin-2.

  Nov. 2002, Brain research, 956(1) (1), 67 - 73, English, International magazine

  Scientific journal


• Brain regions involved in fatigue sensation: reduced acetylcarnitine uptake into the brain.

  Hirohiko Kuratsune, Kouzi Yamaguti, Gudrun Lindh, Birgitta Evengård, Gisela Hagberg, Kiyoshi Matsumura, Masao Iwase, Hirotaka Onoe, Mamoru Takahashi, Takashi Machii, Yuzuru Kanakura, Teruo Kitani, Bengt Långström, Yasuyoshi Watanabe

  Fatigue is an indispensable sense for ordering rest. However, the neuronal and molecular mechanisms of fatigue remain unclear. Chronic fatigue syndrome (CFS) with long-lasting fatigue sensation seems to be a good model for studying these mechanisms underlying fatigue sensation. Recently, we found that most patients with CFS showed a low level of serum acetylcarnitine, which well correlated with the rating score of fatigue, and that a considerable amount of acetyl moiety of serum acetylcarnitine is taken up into the brain. Here we show by metabolite analysis of the mouse brain that an acetyl moiety taken up into the brain through acetylcarnitine is mainly utilized for the biosynthesis of glutamate. When we studied the cerebral uptake of acetylcarnitine by using [2-(11)C]acetyl-L-carnitine in 8 patients with CFS and in 8 normal age- and sex-matched controls, a significant decrease was found in several regions of the brains of the patient group, namely, in the prefrontal (Brodmann's area 9/46d) and temporal (BA21 and 41) cortices, anterior cingulate (BA24 and 33), and cerebellum. These findings suggest that the levels of biosynthesis of neurotransmitters through acetylcarnitine might be reduced in some brain regions of chronic fatigue patients and that this abnormality might be one of the keys to unveiling the mechanisms of the chronic fatigue sensation.

  Nov. 2002, NeuroImage, 17(3) (3), 1256 - 65, English, International magazine

  Scientific journal


• Neural substrates of human facial expression of pleasant emotion induced by comic films: a PET Study.

  Masao Iwase, Yasuomi Ouchi, Hiroyuki Okada, Chihiro Yokoyama, Shuji Nobezawa, Etsuji Yoshikawa, Hideo Tsukada, Masaki Takeda, Ko Yamashita, Masatoshi Takeda, Kouzi Yamaguti, Hirohiko Kuratsune, Akira Shimizu, Yasuyoshi Watanabe

  Laughter or smile is one of the emotional expressions of pleasantness with characteristic contraction of the facial muscles, of which the neural substrate remains to be explored. This currently described study is the first to investigate the generation of human facial expression of pleasant emotion using positron emission tomography and H(2)(15)O. Regional cerebral blood flow (rCBF) during laughter/smile induced by visual comics and the magnitude of laughter/smile indicated significant correlation in the bilateral supplementary motor area (SMA) and left putamen (P < 0.05, corrected), but no correlation in the primary motor area (M1). In the voluntary facial movement, significant correlation between rCBF and the magnitude of EMG was found in the face area of bilateral M1 and the SMA (P < 0.001, uncorrected). Laughter/smile, as opposed to voluntary movement, activated the visual association areas, left anterior temporal cortex, left uncus, and orbitofrontal and medial prefrontal cortices (P < 0.05, corrected), whereas voluntary facial movement generated by mimicking a laughing/smiling face activated the face area of the left M1 and bilateral SMA, compared with laughter/smile (P < 0.05, corrected). We demonstrated distinct neural substrates of emotional and volitional facial expression and defined cognitive and experiential processes of a pleasant emotion, laughter/smile.

  Oct. 2002, NeuroImage, 17(2) (2), 758 - 68, English, International magazine

  Scientific journal


• Functional anatomy of chemical senses in the alert monkey revealed by positron emission tomography.

  Masayuki Kobayashi, Tetsuya Sasabe, Masaki Takeda, Yusuke Kondo, Shin-Ichi Yoshikubo, Kazuyuki Imamura, Hirotaka Onoe, Tohru Sawada, Yasuyoshi Watanabe

  Functional imaging technique using positron emission tomography (PET) has made it possible to localize functional brain regions in the human brain by detecting changes in regional cerebral blood flow (rCBF). Performing PET studies in the monkey will aid in integrating monkey electrophysiological research with human PET studies. We examined changes in rCBF during olfactory or combined olfactory and gustatory (flavour) stimulation using PET in the alert rhesus monkey. Olfactory or flavour stimulation with acetic acid or apple increased rCBF in the prepyriform area, substantia innominata and amygdala. Besides these areas, flavour stimulation increased rCBF in the anterior insula and frontal operculum, orbitofrontal cortex, inferior frontal gyrus and cerebellum. Apple odour or flavour stimuli increased rCBF in the inferior occipital gyrus in addition to the above areas. These findings suggest that the increases of rCBF in response to neural activities in the primary olfactory and gustatory cortices are detectable by the use of PET. In addition, regions activated by apple stimuli suggest that higher brain function might be detected with PET in the alert monkey.

  Sep. 2002, The European journal of neuroscience, 16(5) (5), 975 - 80, English, International magazine

  Scientific journal


• In vitro autoradiographic localization of (125)i-secretin receptor binding sites in rat brain.

  Satoshi Nozaki, Rika Nakata, Hiroshi Mizuma, Nobuhiro Nishimura, Yumiko Watanabe, Ryuichiro Kohashi, Yasuyoshi Watanabe

  Although the existence of the receptor for secretin in the brain was suggested, the localization of secretin receptor and the neuronal function of secretin have not been clarified yet. In the present study, the localization of secretin receptor was investigated in the rat brain by using an in vitro autoradiography technique. Frozen section autoradiography with (125)I-secretin showed intense binding in the nucleus of solitary tract, laterodorsal thalamic nucleus, and accumbens nucleus; moderate binding in the hippocampus, caudate/putamen, cerebellum, cingulate and orbital cortices. Scatchard plot analysis gave the Kd value of 125 pM with Bmax of 134 fmol/mg tissue in the hippocampus. The binding specificity was confirmed with secretin and its analogs, VIP, PACAP, and glucagon. These results indicate the secretin receptor system might have some neural functions in the brain, which could give the basis for therapeutic use of secretin in autistic children.

  Mar. 2002, Biochemical and biophysical research communications, 292(1) (1), 133 - 7, English, International magazine

  Scientific journal


• A positron-emitter labeled glycine(B) site antagonist, [(11)C]L-703,717, preferentially binds to a cerebellar NMDA receptor subtype consisting of GluR epsilon3 subunit in vivo, but not in vitro.

  Terushi Haradahira, Takashi Okauchi, Jun Maeda, Ming-Rong Zhang, Takayo Kida, Kouichi Kawabe, Masayoshi Mishina, Yasuyoshi Watanabe, Kazutoshi Suzuki, Tetsuya Suhara

  In previous studies, we have found that [(11)C]L-703,717, a positron-emitter labeled antagonist for the glycine-binding site of NMDA receptors, only localizes in rodent cerebellum under in vivo conditions. In order to understand the unusual cerebellar localization, we have examined the binding of [(11)C]L-703,717 to a cerebellar-specific NMDA receptor subtype consisting of GLuRepsilon3 subunit, by comparing its autoradiographic distributions between GluRepsilon3-deficient and wild-type mice. Ex vivo [(11)C]L-703,717 binding to wild-type mice showed a highly specific localization of radioactivity in the cerebellum, whereas that to the GluRepsilon3-deficient mice showed no specific localization of radioactivity in any of the brain regions. In contrast to the ex vivo binding, in vitro [(11)C]L-703,717 binding displayed a similar binding characteristic between GluRepsilon3-deficient and wild-type mice with highly specific localizations in the hippocampus and cerebral cortex. Therefore, the present study clearly demonstrated that [(11)C]L-703,717 preferentially binds to a cerebellar NMDA receptor subtype consisting of GluRepsilon3 subunit in vivo, but not in vitro.

  Feb. 2002, Synapse (New York, N.Y.), 43(2) (2), 131 - 3, English, International magazine

  Scientific journal


• A Novel Subtype of Prostacyclin Receptor in the Central Nervous System

  Yumiko Watanabe, Kiyoshi Matsumura, Hajime Takechi, Koichi Kato, Hiroshi Morii, Margareta Björkman, Bengt Langstrom, Ryoji Noyori, Masaaki Suzuki, Yasuyoshi Watanabe

  Wiley, Jan. 2002, Journal of Neurochemistry, 72(6) (6), 2583 - 2592

  [Refereed]

  Scientific journal


• Nonneurogenic hypoxia sensitivity in rat adrenal slices

  Y Takeuchi, N Mochizuki-Oda, H Yamada, K Kurokawa, Y Watanabe

  Nov. 2001, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 289(1) (1), 51 - 56, English

  [Refereed]

  Scientific journal


• Increase of interstitial glycerol reflects the degree of ischaemic brain damage: a PET and microdialysis study in a middle cerebral artery occlusion-reperfusion primate model

  P Frykholm, L Hillered, B Langstrom, L Persson, J Valtysson, Y Watanabe, P Enblad

  Oct. 2001, JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, 71(4) (4), 455 - 461, English

  [Refereed]

  Scientific journal


• 生後発達に伴うセロトニン受容体2Aと2Cの発現パターンの変化

  李 慶華, 中舘 和彦, 田中 佐和子[中舘], 中塚 大策, 野崎 聡, 崔 翼龍, 渡辺 恭良

  日本神経化学会, Sep. 2001, 神経化学, 40(2-3) (2-3), 302 - 302, Japanese


• 中枢神経組織酸化モデルにおける組織抗酸化能力及びモノアミン動態の変化

  崔 翼龍, 片岡 洋祐, 野崎 聡, 田村 泰久, 林 要人, 宇都宮 一泰, 植田 勇人, 三山 吉夫, 山田 久夫, 渡辺 恭良

  日本神経化学会, Sep. 2001, 神経化学, 40(2-3) (2-3), 399 - 399, Japanese


• 培養中枢ニューロンの静止膜電位及び膜抵抗に対する近赤外レーザー光の作用

  田村 泰久, 片岡 洋祐, 小田 紀子[望月], 崔 翼龍, 渡辺 恭良, 山田 久夫

  日本神経化学会, Sep. 2001, 神経化学, 40(2-3) (2-3), 400 - 400, Japanese


• 中枢神経系におけるGTPシクロヒドロラーゼIの局在と発達変化

  中舘 和彦, 田中 佐和子[中舘], 今村 一之, Hirayama Kei, Kapatos Gregory, 渡辺 恭良

  (株)ライフ・サイエンス, Aug. 2001, Progress in Medicine, 21(8) (8), 1949 - 1954, Japanese


• Activity-dependent neural tissue oxidation emits intrinsic ultraweak photons

  Y Kataoka, YL Cui, A Yamagata, M Niigaki, T Hirohata, N Oishi, Y Watanabe

  Jul. 2001, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 285(4) (4), 1007 - 1011, English

  [Refereed]

  Scientific journal


• Synthesis of a11C-labelled prostaglandin F2α analogue using an improved method for stille reactions with [11C]methyl iodide

  Margareta Björkman, Hisashi Doi, Bahram Resul, Masaaki Suzuki, Ryoji Noyori, Yasuyoshi Watanabe, Bengt L{\aa}ngström

  Wiley, Dec. 2000, Journal of Labelled Compounds and Radiopharmaceuticals, 43(14) (14), 1327 - 1334, English

  Scientific journal


• Designed prostaglandins with neurotrophic activities

  K Furuta, K Tomokiyo, T Satoh, Y Watanabe, M Suzuki

  Nov. 2000, CHEMBIOCHEM, 1(4) (4), 283 - 286, English

  [Refereed]

  Scientific journal


• Rapid methylation for the synthesis of a ¹¹C-labeled tolylisocarbacyclin imaging the IP2 receptor in a living human brain

  Masaaki Suzuki, Hisashi Doi, Koichi Kato, Margareta Björkman, Bengt Långström, Yasuyoshi Watanabe, Ryoji Noyori

  Oct. 2000, Tetrahedron, 56(42) (42), 8263 - 8273

  Scientific journal


• Designed cyclopentenone prostaglandin derivatives as neurite outgrowth-promoting compounds for CAD cells, a rat catecholaminergic neuronal cell line of the central nervous system

  T Satoh, K Furuta, K Tomokiyo, M Suzuki, Y Watanabe

  Sep. 2000, NEUROSCIENCE LETTERS, 291(3) (3), 167 - 170, English

  [Refereed]

  Scientific journal


• Neovascularization with blood-brain barrier breakdown in delayed neuronal death.

  Y Kataoka, Y Cui, H Yamada, K Utsunomiya, H Niiya, H Yanase, Y Nakamura, A Mitani, K Kataoka, Y Watanabe

  Various kinds of acute pathological events in the central nervous system, such as ischemia, hemorrhage, and trauma, often cause brain edema. The edema may advance for days or weeks while inducing extensive damage in neural function, regardless of the extent of the original damage, and often results in death. Delayed edema is thought to be vasogenic; however, the mechanism underlying edema induction remains unknown. We found delayed vascular cell proliferation with a blood-brain barrier breakdown in and around the gerbil CA1 hippocampus, a region known to be involved in delayed apoptotic neuronal death 2-6 days after transient ischemia. Vascular cell proliferation, assessed by (3)H-thymidine incorporation, was most prominent 4-6 days after ischemia, and extravasation of exogenously applied dye or endogenous serum albumin from blood vessels was observed concomitantly. We propose neovascularization in delayed neuronal death as a cause of brain edema advancing days after neurological events.

  Jul. 2000, Biochemical and biophysical research communications, 273(2) (2), 637 - 41, English, International magazine

  Scientific journal


• Molecular design of prostaglandin probes in brain research: High, specific binding to a novel prostacyclin receptor in the central nervous system

  Masaaki Suzuki, Ryoji Noyori, Bengt Långström, Yasuyoshi Watanabe

  May 2000, Bulletin of the Chemical Society of Japan, 73(5) (5), 1053 - 1070

  Scientific journal


• 脳発達とGTP Cyclohydrolase

  渡辺 恭良, 田中 佐和子[中舘], 中舘 和彦, 今村 一之

  (公社)日本ビタミン学会, Dec. 1999, ビタミン, 73(12) (12), 754 - 754, Japanese


• Protective effect of prostaglandin I-2 analogs on ischemic delayed neuronal damage in gerbils

  YL Cui, Y Kataoka, T Satoh, A Yamagata, N Shirakawa, Y Watanabe, M Suzuki, H Yanase, K Kataoka, Y Watanabe

  Nov. 1999, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 265(2) (2), 301 - 304, English

  [Refereed]

  Scientific journal


• Effects of monocular enucleation on parvalbumin in rat visual system during postnatal development

  Yoritsugu Hada, Yuko Yamada, Kazuyuki Imamura, Nobuko Mataga, Yasuyoshi Watanabe, Misao Yamamoto

  Oct. 1999, Investigative Ophthalmology and Visual Science, 40(11) (11), 2535 - 2545, English

  Scientific journal


• CNS-specific prostacyclin ligands as neuronal survival-promoting factors in the brain

  T Satoh, Y Ishikawa, Y Kataoka, YL Cui, H Yanase, K Kato, Y Watanabe, K Nakadate, K Matsumura, H Hatanaka, K Kataoka, R Noyori, M Suzuki, Y Watanabe

  Sep. 1999, EUROPEAN JOURNAL OF NEUROSCIENCE, 11(9) (9), 3115 - 3124, English

  [Refereed]

  Scientific journal


• Developmental regulation of intracellular calcium by N-methyl-D- aspartate and noradrenaline in rat visual cortex

  M. Kobayashi, K. Imamura, P. A. Kaub, K. Nakadate, Y. Watanabe

  Jun. 1999, Neuroscience, 92(4) (4), 1309 - 1322, English

  [Refereed]

  Scientific journal


• Prostaglandin J(2) and its metabolites promote neurite outgrowth induced by nerve growth factor in PC12 cells

  T Satoh, K Furuta, M Suzuki, Y Watanabe

  Apr. 1999, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 258(1) (1), 50 - 53, English

  [Refereed]

  Scientific journal


• 15-Deoxy-16-(m-tolyl)-17,18,19,20-tetranorisocarbacyclin: A simple TIC derivative with potent anti-apoptotic activity for neuronal cells

  Masaaki Suzuki, Koichi Kato, Yumiko Watanabe, Takumi Satoh, Kiyoshi Matsumura, Yasuyoshi Watanabe, Ryoji Noyori

  Feb. 1999, Chemical Communications, (4) (4), 307 - 308

  Scientific journal


• Differential expression of immediate-early genes, c-fos and zif268, in the visual cortex of young rats: Effects of a noradrenergic neurotoxin on their expression

  Y Yamada, Y Hada, K Imamura, N Mataga, Y Watanabe, M Yamamoto

  1999, NEUROSCIENCE, 92(2) (2), 473 - 484, English

  [Refereed]

  Scientific journal


• 発達異常視覚野におけるc-FOSタンパクの発現様式

  今村 一之, 中舘 和彦, 小林 真之, Kaub Peter A., 渡辺 恭良

  日本神経化学会, Sep. 1998, 神経化学, 37(3) (3), 527 - 527, Japanese


• 嗅覚研究の最前線 PET・fMRIを用いた嗅覚系の解析

  渡辺 恭良, 今村 一之, 小林 真之, 片岡 洋祐, 尾上 浩隆, 中舘 和彦, 駒井 章治, 吉久保 真一, 服部 慶明, 永井 康雄

  (一社)日本鼻科学会, Aug. 1998, 日本鼻科学会会誌, 37(3) (3), 170 - 170, Japanese


• Synthesis of ¹¹C/¹³C-labelled prostacyclins

  Margarete Björkman, Yvonne Andersson, Hisashi Doi, Koichi Kato, Masaaki Suzuki, Ryoji Noyori, Yasuyoshi Watanabe, Bengt Långström

  May 1998, Acta Chemica Scandinavica, 52(5) (5), 635 - 640

  Scientific journal


• Cyclooxygenase-2 is induced in brain blood vessels during fever evoked by peripheral or central administration of tumor necrosis factor

  Chunyu Cao, Kiyoshi Matsumura, Kanato Yamagata, Yasuyoshi Watanabe

  May 1998, Molecular Brain Research, 56(1-2) (1-2), 45 - 56, English

  [Refereed]

  Scientific journal


• Low levels of serum acylcarnitine in chronic fatigue syndrome and chronic hepatitis type C? but not seen in other diseases

  Hirohiko Kuratsune, Kouzi Yamaguti, Gudrun Lindh, Birgitta Evengård, Mamoru Takahashi, Takashi Machii, Kiyoshi Matsumura, Joh Takaishi, Sumio Kawata, Bengt Långström, Yuzuru Kanakura, Teruo Kitani, Yasuyoshi Watanabe

  Spandidos Publications, 1998, International Journal of Molecular Medicine, 2(1) (1), 51 - 56, English

  Scientific journal


• Role of brain endothelial cyclooxygenase-2 in the transmission of immune signal to the central nervous system

  K Matsumura, CY Cao, K Nakadate, H Morii, Y Watanabe

  1998, BRAIN AND BIODEFENCE, 21, 99 - 109, English

  [Refereed]

  International conference proceedings


• Rapid coupling of methyl iodide with aryltributylstannanes mediated by palladium(0) complexes: A general protocol for the synthesis of ¹¹CH3-labeled PET tracers

  Masaaki Suzuki, Hisashi Doi, Margareta Björkman, Yvonne Andersson, Bengt Långström, Yasuyoshi Watanabe, Ryoji Noyori

  Dec. 1997, Chemistry - A European Journal, 3(12) (12), 2039 - 2042

  Scientific journal


• A postsynaptic excitatory amino acid transporter with chloride conductance functionally regulated by neuronal activity in cerebellar Purkinje cells

  Y Kataoka, H Morii, Y Watanabe, H Ohmori

  Sep. 1997, JOURNAL OF NEUROSCIENCE, 17(18) (18), 7017 - 7024, English

  [Refereed]

  Scientific journal


• Effects of monocular enucleation on receptor binding and innervation pattern of the noradrenergic system in the superior colliculus of the pigmented rat

  Keiko Muguruma, Kiyoshi Matsumura, Yumiko Watanabe, Tsuyoshi Shiomitsu, Kazuyuki Imamura, Yasuyoshi Watanabe

  Aug. 1997, Neuroscience Research, 28(4) (4), 311 - 324, English

  Scientific journal


• Involvement of cyclooxygenase-2 in LPS-induced fever and regulation of its mRNA by LPS in the rat brain

  CY Cao, K Matsumura, K Yamagata, Y Watanabe

  Jun. 1997, AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY, 272(6) (6), R1712 - R1725, English

  [Refereed]

  Scientific journal


• Hypoxia-induced catecholamine release and intracellular Ca2+ increase via suppression of K+ channels in cultured rat adrenal chromaffin cells

  Noriko Mochizuki-Oda, Yuko Takeuchi, Kiyoshi Matsumura, Yoshio Oosawa, Yasuyoshi Watanabe

  Blackwell Publishing Ltd, 1997, Journal of Neurochemistry, 69(1) (1), 377 - 387, English

  Scientific journal


• Possible role of cyclooxygenase-2 in the brain vasculature in febrile response

  K Matsumura, CY Cao, Y Watanabe

  1997, THERMOREGULATION, 813, 302 - 306, English

  [Refereed]

  Scientific journal


• Enhancement of mRNA expression of tissue-type plasminogen activator by L-threo-3,4-dihydroxyphenylserine in association with ocular dominance plasticity

  N Mataga, K Imamura, T Shiomitsu, Y Yoshimura, F Fukamauchi, Y Watanabe

  Nov. 1996, NEUROSCIENCE LETTERS, 218(3) (3), 149 - 152, English

  [Refereed]

  Scientific journal


• Down-regulation of beta-adrenergic receptor following long-term monocular deprivation in cat visual cortex

  K Muguruma, K Imamura, H Morii, Y Watanabe

  Nov. 1996, BRAIN RESEARCH, 740(1-2) (1-2), 131 - 140, English

  [Refereed]

  Scientific journal


• Repeated peripheral administration of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin alters the binding activities of 5-HT1A and 5-HT2 receptors in rat brain

  K Muguruma, K Imamura, Y Watanabe

  Oct. 1996, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 227(3) (3), 794 - 799, English

  [Refereed]

  Scientific journal


• Endothelial cells of the rat brain vasculature express cyclooxygenase-2 mRNA in response to systemic interleukin-1β: A possible site of prostaglandin synthesis responsible for fever

  Chunyu Cao, Kiyoshi Matsumura, Kanato Yamagata, Yasuyoshi Watanabe

  Elsevier B.V., Sep. 1996, Brain Research, 733(2) (2), 263 - 272, English

  [Refereed]

  Scientific journal


• Acylcarnitine metabolism during fasting and after refeeding

  Kouzi Yamaguti, Hirohiko Kuratsune, Yasuyoshi Watanabe, Mamoru Takahashi, Ichiro Nakamoto, Takashi Machii, Gunilla Jacobsson, Hirotaka Onoe, Kiyoshi Matsumura, Sven Valind, Bengt Långström, Teruo Kitani

  Academic Press Inc., Aug. 1996, Biochemical and Biophysical Research Communications, 225(3) (3), 740 - 746, English

  Scientific journal


• A novel subtype of the prostacyclin receptor expressed in the central nervous system

  Hajime Takechi, Kiyoshi Matsumura, Yumiko Watanabe, Koichi Kato, Ryoji Noyori, Masaaki Suzuki, Yasuyoshi Watanabe

  Mar. 1996, Journal of Biological Chemistry, 271(10) (10), 5901 - 5906

  Scientific journal


• (15R)-16-m-Tolyl-17,18,19,20-tetranorisocarbacyclin: A Stable Ligand with High Binding Affinity and Selectivity for a Prostacyclin Receptor in the Central Nervous System

  Masaaki Suzuki, Koichi Kato, Ryoji Noyori, Yumiko Watanabe, Hajime Takechi, Kiyoshi Matsumura, Bengt Långström, Yasuyoshi Watanabe

  Wiley, Feb. 1996, Angewandte Chemie International Edition in English, 35(3) (3), 334 - 336

  [Refereed]

  Scientific journal


• 41 DESIGN AND SYNTHESIS OF A MOLECULAR PROBE SPECIFIC FOR A NOVEL SUBTYPE OF PROSTACYCLIN RECEPTOR IN THE CENTRAL NERVOUS SYSTEM

  Suzuki Masaaki, Hosoya Takamitsu, Takeuchi Kyoko, Kato Koichi, Fukunaga Hirofumi, Noyori Ryoji, Watanabe Yumiko, Matsumura Kiyoshi, Takechi Hajime, Watanabe Yasuyoshi, Langstrom Bengt

  Recently, the role of prostaglandins (PGs) in brain function has attracted much attention. We succeeded in creating a stable ligand with high binding affinity and selectivity for a prostacyclin (1, PGI_2) receptor expressed in the central nervous system (CNS). The ligand, (15R)-16-m-tolyl-17,18,19,20-tetranorisocarbacyclin (3, 15R-TIC), was prepared starting from the Horner-Emmons reaction of aldehyde 4 and β-keto phosphonate 5 followed by 1,2-reduction of the enone, separation of the resulting C(15)-epimers, and hydrolysis of the methyl ester. The binding assay was conducted by the [^3H]isocarbacyclin displacement study using the rat frozen tissue sections containing the thalamus or NTS (nucleus tractus solitarius) as representative of the CNS or peripheral nervous system. Consequently, 3 exhibited high binding affinity sufficient for a receptor in the thalamus (IP_2) but showed very weak binding for a receptor in the NTS (IP_1). In contrast, cicaprost (12), a stable PGI_2 agonist belonging to an iloprost family, showed high binding affinity and selectivity for IP_1. 15S-TIC (9), the C(15)-epimer of 3, and isocarbacyclin (2) bound strongly with both of the receptors. Electrophysiological studies carried out in the CA1 region of the rat hippocampus revealed that the PGI_2 analogs have a facilitatory effect on the excitatory transmission through IP_2. The widespread expression of IP_2 in the CNS suggests that PGI_2 has important roles in neuronal activity. In order to identify IP_2, we prepared an azido-functionalized isocarbacyclin derivative 14 as a photoaffinity probe, which showed strong binding affinity for IP_2.

  Symposium on the Chemistry of Natural Products Steering Committee, 1996, Symposium on the Chemistry of Natural Products, symposium papers, 38, 241 - 246, Japanese


• Induction by lipopolysaccharide of cyclooxygenase-2 mRNA in rat brain; its possible role in the febrile response

  Chunyu Cao, Kiyoshi Matsumura, Kanato Yamagata, Yasuyoshi Watanabe

  Oct. 1995, Brain Research, 697(1-2) (1-2), 187 - 196, English

  [Refereed]

  Scientific journal


• PROSTAGLANDIN-E2 EXCITES NEURONS OF THE NUCLEUS-TRACTUS-SOLITARIUS BY ACTIVATING CATION CHANNELS

  K MATSUMURA, Y WATANABE, H ONOE, Y WATANABE, S TANAKA, T SHIRAKI, S KOBAYASHI

  Oct. 1993, BRAIN RESEARCH, 626(1-2) (1-2), 343 - 346, English

  [Refereed]


• BEHAVIORAL ACTIVATION BY STIMULATION OF A GABAERGIC MECHANISM IN THE PREOPTIC AREA OF RAT

  PG OSBORNE, N MATAGA, H ONOE, Y WATANABE

  Aug. 1993, NEUROSCIENCE LETTERS, 158(2) (2), 201 - 204, English

  [Refereed]

  Scientific journal


• REGULATION OF PROSTAGLANDIN-D(2)-RECEPTOR AND PROSTAGLANDIN-E(2)-RECEPTOR BINDING IN THE CENTRAL-NERVOUS-SYSTEM

  H MORII, Y WATANABE

  Mar. 1993, JOURNAL OF LIPID MEDIATORS, 6(1-3) (1-3), 445 - 451, English

  [Refereed]

  Scientific journal


• GLIOTOXIN-INDUCED SUPPRESSION OF OCULAR DOMINANCE PLASTICITY IN KITTEN VISUAL-CORTEX

  K IMAMURA, N MATAGA, Y WATANABE

  Feb. 1993, NEUROSCIENCE RESEARCH, 16(2) (2), 117 - 124, English

  [Refereed]

  Scientific journal


• L-THREO-3,4-DIHYDROXYPHENYLSERINE ENHANCED OCULAR DOMINANCE PLASTICITY IN ADULT CATS

  N MATAGA, K IMAMURA, Y WATANABE

  Aug. 1992, NEUROSCIENCE LETTERS, 142(2) (2), 115 - 118, English

  [Refereed]

  Scientific journal


• A NOVEL ROLE OF 6R-TETRAHYDROBIOPTERIN IN THE CENTRAL-NERVOUS-SYSTEM

  N MATAGA, K IMAMURA, Y WATANABE

  1992, NEUROBIOLOGY OF INFANTILE AUTISM, 965, 333 - 334, English

  [Refereed]

  International conference proceedings


• A NOVEL ROLE OF 6R-TETRAHYDROBIOPTERIN - MICRODIALYSIS AND ELECTROPHYSIOLOGICAL STUDIES

  N MATAGA, K IMAMURA, Y WATANABE

  1992, FRONTIERS AND NEW HORIZONS IN AMINO ACID RESEARCH, 541 - 545, English

  [Refereed]

  International conference proceedings


• A POSSIBLE ROLE OF CARBOHYDRATE MOIETIES IN PROSTAGLANDIN-D2 AND PROSTAGLANDIN-E2 RECEPTOR PROTEINS FROM THE PORCINE TEMPORAL CORTEX

  H MORII, Y WATANABE

  Jan. 1992, ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 292(1) (1), 121 - 127, English

  [Refereed]

  Scientific journal


• REGULATION OF PROSTAGLANDIN-E2 RECEPTOR-BINDING ACTIVITY IN PORCINE TEMPORAL CORTEX BY PROTEIN-PHOSPHORYLATION

  H MORII, M TANEMURA, Y WATANABE

  Oct. 1991, JOURNAL OF NEUROCHEMISTRY, 57(4) (4), 1281 - 1287, English

  [Refereed]

  Scientific journal


• 6R-TETRAHYDROBIOPTERIN PERFUSION ENHANCES DOPAMINE, SEROTONIN, AND GLUTAMATE OUTPUTS IN DIALYSATE FROM RAT STRIATUM AND FRONTAL-CORTEX

  N MATAGA, K IMAMURA, Y WATANABE

  Jun. 1991, BRAIN RESEARCH, 551(1-2) (1-2), 64 - 71, English

  [Refereed]

  Scientific journal


• SOLUBILIZATION OF PROSTAGLANDIN-D2 BINDING-PROTEIN FROM PORCINE TEMPORAL CORTEX

  H MORII, Y WATANABE

  Jan. 1991, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 174(1) (1), 364 - 371, English

  [Refereed]

  Scientific journal

• カルシウム摂取不足が血中25-hydroxyvitamin D濃度に与える影響 横断的疫学調査による検討

  津川 尚子, 桑原 晶子, 浦 千尋, 小笠原 帆南, 田中 清, 水野 敬, 渡辺 恭良

  (公社)日本ビタミン学会, Apr. 2022, ビタミン, 96(4) (4), 204 - 204, Japanese


• 擬似ウイルス感染モデルラットでの脳内炎症は倦怠感の惹起に関わる

  越智祐太, 新垣和貴子, 胡迪, 李丹渓, 重田美香, 林中恵美, 和田康弘, 土居久志, 渡辺恭良, 崔翼龍

  2022, 日本神経化学会大会抄録集(Web), 65th


• 条件付け誘発性のプラセボ鎮痛はmedial prefrontal cortex-ventrolateral periaqueductal gray回路の活性化を介する

  根山広行, 武玉萍, 井上美智子, 清水朋子, 加藤成樹, 渡辺恭良, 小林和人, 崔翼龍

  2022, 日本神経化学会大会抄録集(Web), 65th


• 慢性疲労症候群における筋力低下に伴う影響

  田中 邦彦, 福田 早苗, 山口 浩二, 渡辺 恭良, 倉恒 弘彦

  日本疲労学会, May 2019, 日本疲労学会誌, 15(1) (1), 69 - 69, Japanese


• 慢性疲労症候群における筋力低下に伴う影響

  田中 邦彦, 福田 早苗, 山口 浩二, 渡辺 恭良, 倉恒 弘彦

  日本疲労学会, May 2019, 日本疲労学会誌, 15(1) (1), 69 - 69, Japanese


• 半導体コンプトンカメラGREIによるNa+/K+の同時イメージング

  本村 信治, 喜井 勲, 羽場 宏光, 薬師寺 秀樹, 渡辺 恭良, 榎本 秀一

  日本分子イメージング学会, May 2019, JSMI Report, 12(2) (2), 170 - 170, Japanese


• 慢性疲労症候群におけるフレイルの状況と日常生活への影響

  田中 邦彦, 福田 早苗, 雪野 皐月, 山口 浩二, 松本 美富士, 渡辺 恭良, 倉恒 弘彦

  日本疲労学会, May 2018, 日本疲労学会誌, 14(1) (1), 63 - 63, Japanese


• 健常者を対象とした疲労感想起に関与する神経メカニズムの解明

  山野 恵美, 石井 聡, 田中 雅彰, 渡辺 恭良

  日本疲労学会, May 2018, 日本疲労学会誌, 14(1) (1), 56 - 56, Japanese

  [Refereed]


• Drug development accelerated by PET imaging-based pharmacokinetics and DDS research

  Hidefumi Mukai, Yasuyoshi Watanabe

  Japan Society of Drug Delivery System, 2018, Drug Delivery System, 33(3) (3), 204 - 213, Japanese

  Book review


• バイオイメージングの創薬、診断、治療への展開 がんと炎症の差別化イメージング

  野崎 聡, 笹野 有未, 山本 憲一郎, 馬渡 彩, 柴田 仁奈, 中谷 友香, 尾上 嘉代, 和田 康弘, 露口 尚弘, 土居 久志, 児玉 和也, 渡辺 恭良

  日本癌学会, Sep. 2017, 日本癌学会総会記事, 76回, S15 - 4, English


• メンケス病モデルマウスにおける銅キレート剤ジスルフィラムを用いた銅の経口投与についての検討

  保科 隆男, 野崎 聡, 濱崎 考史, 山下 加奈子, 佐久間 悟, 瀬戸 俊之, 中谷 友香, 児玉 浩子, 渡辺 恭良, 新宅 治夫

  (一社)日本小児神経学会, May 2017, 脳と発達, 49(Suppl.) (Suppl.), S453 - S453, Japanese


• 慢性疲労症候群の栄養摂取状況と疲労度との関連

  田中 邦彦, 福田 早苗, 雪野 皐月, 山口 浩二, 渡邊 恭良, 倉恒 弘彦

  日本疲労学会, May 2017, 日本疲労学会誌, 13(1) (1), 74 - 74, Japanese


• 慢性疲労症候群における筋質評価の検討

  雪野 皐月, 福田 早苗, 田中 邦彦, 内山 朋香, 山口 浩二, 渡邊 恭良, 倉恒 弘彦

  日本疲労学会, May 2017, 日本疲労学会誌, 13(1) (1), 76 - 76, Japanese


• ME/CFS患者における睡眠時身体活動と心拍変動の相互関連を通じた睡眠の質的評価の試み

  山口 浩二, 笹部 哲也, 中富 康仁, 田中 邦彦, 福田 早苗, 倉恒 弘彦, 稲葉 雅章, 渡邊 恭良

  日本疲労学会, May 2017, 日本疲労学会誌, 13(1) (1), 90 - 90, Japanese


• メタボローム解析による慢性疲労症候群バイオマーカーの開発

  山野 恵美, 杉本 昌弘, 久米 慧嗣, 大和 正典, 田島 世貴, 山口 浩二, 倉恒 弘彦, 福田 早苗, 曽我 朋義, 渡邊 恭良, 片岡 洋祐

  日本疲労学会, May 2017, 日本疲労学会誌, 13(1) (1), 89 - 89, Japanese


• [18F]AA-7 腫瘍特異的アミノ酸トランスポーターを標的とした新規PETトレーサーの開発

  野崎 聡, 笹野 有未, 山本 憲一郎, Hume WE, 和田 康弘, 石井 聡, 田中 雅彰, 塩見 進, 露口 尚弘, 児玉 和也, 渡辺 恭良

  (一社)日本核医学会, Oct. 2016, 核医学, 53(Suppl.) (Suppl.), S312 - S312, Japanese


• [18F]AA-7 腫瘍特異的アミノ酸トランスポーターを標的とした新規PETトレーサーの開発

  野崎 聡, 大下 智子, 中谷 友香, 笹野 有未, 山本 憲一郎, 林中 恵美, 和田 康弘, 石井 聡, 田中 雅彰, 塩見 進, 露口 尚弘, 児玉 和也, 渡辺 恭良

  日本分子イメージング学会, Apr. 2016, JSMI Report, 9(2) (2), 97 - 97, Japanese


• 慢性疲労症候群の生活習慣 筋肉量低下・筋力・身体能力低下と生活習慣との関連

  榊 弥香, 福田 早苗, 田中 邦彦, 山口 浩二, 山田 真介, 絵本 正憲, 松本 美富士, 渡辺 恭良, 倉恒 弘彦, 稲葉 雅章

  日本疲労学会, Mar. 2016, 日本疲労学会誌, 11(2) (2), 56 - 70, Japanese


• CLINICAL EVALUATION OF OATPs AND MRP2 ACTIVITY USING POSITRON EMISSION TOMOGRAPHY (PET) WITH [C-11]DEHYDROPRAVASTATIN

  Tomotaka Shingaki, Masaaki Tanaka, Akira Ishii, Yumiko Katayama, Shusaku Tazawa, Yasuhiro Wada, Yilong Cui, Kazuya Maeda, Hiroyuki Kusuhara, Yuichi Sugiyama, Yasuyoshi Watanabe

  Nov. 2015, DRUG METABOLISM REVIEWS, 47, 241 - 242, English

  Summary international conference


• 11C-ケトプロフェンメチルエステルS体の生体内分布と被ばく線量評価

  大西 章仁, 千田 道雄, 赤松 剛, 相田 一樹, 佐々木 將博, 山本 泰司, 馬渡 彩, 宿里 充穂, 土居 久志, 渡辺 恭良, 尾上 浩隆

  (一社)日本核医学会, Sep. 2015, 核医学, 52(3) (3), 269 - 269, Japanese


• Human biodistribution and dosimetry of S-enantiomer C-11-ketoprofen methyl ester, a potential PET probe of neuroinflammatory processes for Alzheimer's disease

  Akihito Ohnishi, Michio Senda, Go Akamatsu, Kazuki Aita, Masahiro Sasaki, Yasuji Yamamoto, Miho Shukuri, Hisashi Doi, Yasuyoshi Watanabe, Hirotaka Onoe

  May 2015, JOURNAL OF NUCLEAR MEDICINE, 56(3) (3), English

  Summary international conference


• 細胞膜透過ペプチド併用経鼻投与によるインスリン脳内デリバリー 64Cu-NODAGA標識インスリンを用いた脳内分布評価

  亀井 敬泰, 新垣 友隆, 金山 洋介, 蔵地 理代, 長谷川 功紀, 渡辺 恭良, 武田 真莉子

  (公社)日本薬学会, Mar. 2015, 日本薬学会年会要旨集, 135年会(4) (4), 73 - 73, Japanese


• 次世代生命基盤技術を用いたB型肝炎制圧のための創薬研究 PET分子イメージングによる薬効評価・薬物動態研究

  渡辺恭良, 金山洋介, HUME William Ewan, 張周恩, 丹羽節, 落合秀紀, 隅田有人, 崔翼龍, 佐古健生

  2015, 次世代生命基盤技術を用いたB型肝炎制圧のための創薬研究 平成26年度 総括・分担研究報告書, 74‐77, Japanese


• 分子イメージング技術の最前線とそのDDS研究・臨床へのインパクト 分子イメージング活用創薬とDDS開発

  渡辺 恭良, 向井 英史, 新垣 友隆

  日本DDS学会, Jul. 2014, 日本DDS学会学術集会プログラム予稿集, 30回, 118 - 118, Japanese


• 腫瘍組織内抗癌タンパク産生B.choshinensisの作製と抗腫瘍効果

  向井 英史, 高橋 麻衣子, 渡辺 恭良

  日本DDS学会, Jul. 2014, 日本DDS学会学術集会プログラム予稿集, 30回, 176 - 176, Japanese


• 疲労・睡眠への栄養教育プログラムの構築

  藤井 比佐子, 福田 早苗, 千須和 直美, 渡辺 恭良

  女性健康科学研究会, May 2014, 女性健康科学研究会受賞研究報告集, 3(1) (1), 38 - 42, Japanese


• メタボローム解析による慢性疲労症候群診断バイオマーカーの検討

  山野 恵美, 久米 慧嗣, 大和 正典, 田島 世貴, 福田 早苗, 倉恒 弘彦, 渡辺 恭良, 片岡 洋祐

  日本疲労学会, May 2014, 日本疲労学会誌, 10(1) (1), 69 - 69, Japanese


• 職域集団における疲労とメタボリック症候群との関連について(中間解析結果より)

  藤井 比佐子, 福田 早苗, 小山 英則, 長見 まき子, 倉恒 弘彦, 渡辺 恭良

  日本疲労学会, May 2014, 日本疲労学会誌, 10(1) (1), 78 - 78, Japanese


• 新しいPET分子プローブ(11C-セトロゾール)を用いた難治性てんかんの病態解明へのアプローチ

  露口 尚弘, 高橋 佳代, 和田 康弘, 渡辺 恭良

  (一社)日本てんかん学会, Sep. 2013, てんかん研究, 31(2) (2), 382 - 382, Japanese


• 改善方法と有用性 栄養教育による睡眠と疲労改善効果

  藤井 比佐子, 福田 早苗, 渡辺 恭良

  日本疲労学会, Jun. 2013, 日本疲労学会誌, 9(1) (1), 81 - 81, Japanese


• 機能と評価方法 脳磁図計を用いた精神的ストレスに対する生体反応の個人差に関する検討

  山野 恵美, 田中 雅彰, 石井 聡, 渡辺 恭良

  日本疲労学会, Jun. 2013, 日本疲労学会誌, 9(1) (1), 87 - 87, Japanese


• 遺伝子・核酸デリバリーシステム 核酸医薬・DDS開発におけるPETイメージング

  向井 英史, 渡辺 恭良

  日本DDS学会, Jun. 2013, 日本DDS学会学術集会プログラム予稿集, 29回, 100 - 100, Japanese


• 小動物用PETイメージングによるメンケス病モデルマウスを用いた新規治療法の開発と評価

  野村 志保, 野崎 聡, 濱崎 考史, 二宮 英一, 林中 恵美, 和田 康弘, 渡辺 恭良, 新宅 治夫

  (一社)日本周産期・新生児医学会, Jun. 2013, 日本周産期・新生児医学会雑誌, 49(2) (2), 631 - 631, Japanese


• 疲労、睡眠の質、自律神経機能と血中Brain-derived neurotrophic factorの相互関係

  神崎 暁慶, 角谷 学, 蔵城 雅文, 庄司 拓仁, 白石 順, 角田 千尋, 森脇 優司, 山本 徹也, 福田 早苗, 渡辺 恭良, 小山 英則

  日本疲労学会, Jun. 2013, 日本疲労学会誌, 9(1) (1), 59 - 59, Japanese


• Realization of [C-11]CH3-incorporated thiamine and fursultiamin for PET molecular imaging of vitamin B-1

  Hisashi Doi, Aya Mawatari, Masakatsu Kanazawa, Satoshi Nozaki, Yukihiro Nomura, Kouji Akimoto, Shinji Ninomiya, Masaaki Suzuki, Yasuyoshi Watanabe

  May 2013, JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS, 56, S98 - S98, English

  Summary international conference


• 慢性疲労症候群及び一般住民集団における疲労の重症度評価質問票とパフォーマンスステイタス評価の比較

  福田 早苗, 谷畑 健生, 山口 浩二, 中富 康仁, 渡辺 恭良, 倉恒 弘彦

  日本疲労学会, Mar. 2013, 日本疲労学会誌, 8(2) (2), 53 - 59, Japanese


• 次世代生命基盤技術を用いたB型肝炎制圧のための創薬研究 有効・安全性評価に関する研究 PET分子イメージングによる薬効評価・薬物動態研究

  渡辺恭良, EWAN Hume William, 金山洋介, 八塩桂司, 崔翼龍

  2013, 次世代生命基盤技術を用いたB型肝炎制圧のための創薬研究 平成24年度総括・分担研究報告書


• Biochemical indices of fatigue for anti-fatigue strategies and products

  Yasuyoshi Watanabe, Hirohiko Kuratsune, Osami Kajimoto

  01 Dec. 2012, The Handbook of Operator Fatigue, 209 - 224


• げっ歯類および霊長類サルを用いた[11C]Ketoprofen-methyl esterの特性評価

  宿里 充穂, 高島 忠之, 馬渡 彩, 山中 創, 片山 由美子, 千田 道雄, 佐々木 將博, 土居 久志, 鈴木 正昭, 渡辺 恭良, 尾上 浩隆

  (一社)日本核医学会, Aug. 2012, 核医学, 49(3) (3), S249 - S249, Japanese


• 日本におけるCFS 最近の知見 慢性疲労症候群の実態調査

  福田 早苗, 中富 康仁, 山口 浩二, 渡辺 恭良, 倉恒 弘彦

  日本疲労学会, Jun. 2012, 日本疲労学会誌, 8(1) (1), 23 - 23, Japanese


• 大学生における疲労と生活習慣に関する研究

  藤井 比佐子, 福田 早苗, 倉恒 弘彦, 渡辺 恭良

  日本疲労学会, Jun. 2012, 日本疲労学会誌, 8(1) (1), 34 - 34, Japanese


• 抗テネイシンCペプチドアプタマーPETプローブの高感度化に関する検討

  向井 英史, 松村 一史, 川上 茂, 高橋 麻衣子, 造田 真希, 林中 恵美, 山下 富義, 橋田 充, 和田 康弘, 渡辺 恭良

  日本DDS学会, Jun. 2012, 日本DDS学会学術集会プログラム予稿集, 28回, 156 - 156, Japanese


• 64Cu標識CetuximabのEGFR発現がん組織への特異的集積評価

  金山 洋介, 角田 ちぬよ, 田沢 周作, 蔵地 理代, 森本 陽子, 長谷川 功紀, 林中 恵美, 和田 康弘, 高橋 和弘, 渡辺 恭良

  日本分子イメージング学会, May 2012, JSMI Report, 5(2) (2), 121 - 121, Japanese


• 健常人における慢性疲労症候群関連症状38項目による疲労質問票の因子構造と妥当性の検討

  田島 世貴, 中富 康仁, 山口 浩二, 福田 早苗, 小泉 淳一, 稲葉 雅章, 渡辺 恭良, 倉恒 弘彦

  日本疲労学会, Mar. 2012, 日本疲労学会誌, 7(2) (2), 88 - 96, Japanese


• 抗疲労臨床評価ガイドライン 日常生活により問題となる疲労に対する抗疲労製品の効果に関する臨床評価ガイドライン

  渡辺 恭良, 橋本 信也, 倉恒 弘彦, 近藤 一博, 川原 貴, 久保 千春, 下光 輝一, 西澤 良記, 伴 信太郎, 三池 輝久, 松本 美富士, 木谷 照夫, 平山 佳伸, 山口 浩二, 田中 雅彰, 水野 敬, 中富 康仁, 福田 早苗, 日本疲労学会分科会臨床評価ガイドライン委員会

  日本疲労学会, Mar. 2012, 日本疲労学会誌, 7(2) (2), 1 - 13, Japanese


• 小動物用PETを用いたメンケス病モデルマウスでの銅キレート剤投与効果に関する研究

  野村 志保, 野崎 聡, 武田 泰輔, 二宮 英一, 濱崎 考史, 藤岡 弘季, 林中 恵美, 和田 康弘, 渡辺 恭良, 新宅 治夫

  (公社)日本小児科学会, Feb. 2012, 日本小児科学会雑誌, 116(2) (2), 455 - 455, Japanese


• Fatigue-related problem scale for better understanding of pathophysiology of chronic fatigue syndrome and fibromyalgia

  Sanae Fukuda, Hirohiko Kuratsune, Osami Kajimoto, Yasuyoshi Watanabe

  2012, Advances in Neuroimmune Biology, 3(3-4) (3-4), 361 - 366, English


• 3.脳磁図を用いた疲労の脳科学研究(第427回研究協議会研究発表要旨,ビタミンB研究委員会)

  渡辺 恭良, 田中 雅彰, 鴫原 良仁, 石井 聡, 水野 敬, 山野 恵美

  公益社団法人 日本ビタミン学会, 2012, ビタミン, 86(5) (5), 345 - 346, Japanese


• Development of Early Diagnostic Techniques for Rheumatoid Arthritis Using Carbone Eleven Labeled PK11195 and Carbone Eleven Labeled Ketoprofen

  Satoshi Nozaki, Sinobu Suzuki, Naoko Ozaki, Jeffrey Encinas, Hisashi Doi, Yasuhiro Wada, Masaaki Suzuki, Yasuyoshi Watanabe

  Oct. 2011, ARTHRITIS AND RHEUMATISM, 63(10) (10), S74 - S75, English

  Summary international conference


• 慢性疲労up to date 慢性疲労症候群の病態及び実情について

  福田 早苗, 中富 康仁, 山口 浩二, 稲葉 雅章, 渡辺 恭良, 倉恒 弘彦

  日本疲労学会, May 2011, 日本疲労学会誌, 7(1) (1), 39 - 39, Japanese


• 慢性疲労症候群患者と健常者におけるGTP cyclohydrolase I遺伝子多型の解析

  堀口 美恵子, 福田 早苗, 一瀬 宏, 中富 康仁, 山口 浩二, 倉恒 弘彦, 渡辺 恭良

  日本疲労学会, May 2011, 日本疲労学会誌, 7(1) (1), 73 - 73, Japanese


• 慢性疲労症候群における脳内ミクログリア活性化 PET研究

  中富 康仁, 水野 敬, 石井 聡, 和田 康弘, 田中 雅彰, 田沢 周作, 尾上 嘉代, 福田 早苗, 河邉 譲治, 高橋 和弘, 片岡 洋祐, 塩見 進, 山口 浩二, 稲葉 雅章, 倉恒 弘彦, 渡邊 恭良

  日本疲労学会, May 2011, 日本疲労学会誌, 7(1) (1), 66 - 66, Japanese


• 理研CMISにおける64Cu-DOTA-Trastuzumab注射液の治験薬GMP製造への取り組み

  田沢 周作, 長谷川 功紀, 金山 洋介, 蔵地 理代, 森本 陽子, 林 和孝, 立花 晃子, 高橋 和弘, 矢野 恒夫, 渡辺 恭良

  日本分子イメージング学会, May 2011, JSMI Report, 4(2) (2), 116 - 116, Japanese


• 病態モデル動物のライブイメージング 64Cu標識P-セレクチン抗体を用いたLDLレセプター欠損マウスの動脈硬化病変の検出

  中村 郁子, 長谷川 功紀, 和田 康弘, 片岡 洋祐, 大和 正典, 蔵地 理代, 林中 恵美, 平瀬 徹明, 野出 孝一, 渡辺 恭良

  日本分子イメージング学会, May 2011, JSMI Report, 4(2) (2), 33 - 33, Japanese


• 64Cu-DOTA-Trastuzumabの合成法と評価法の確立 A431およびC6腫瘍担持マウスでのPET研究

  長谷川 功紀, 金山 洋介, 角田 ちぬよ, 松本 恭子, 田沢 周作, 蔵地 理代, 森本 陽子, 林中 恵美, 高橋 和弘, 和田 康弘, 渡辺 恭良

  日本分子イメージング学会, May 2011, JSMI Report, 4(2) (2), 114 - 114, Japanese


• Trastuzumabのフラグメント化によるがんイメージングへの影響 担がんマウスを用いたPET研究

  金山 洋介, 長谷川 功紀, 角田 ちぬよ, 林中 恵美, 和田 康弘, 榎本 秀一, 渡辺 恭良

  日本分子イメージング学会, May 2011, JSMI Report, 4(2) (2), 115 - 115, Japanese


• 無麻酔下コモンマーモセットPETを用いた抗精神病薬ルラシドンとオランザピンのドパミンD2受容体占有率の評価

  中澤 俊介, 西村 直浩, 横山 ちひろ, 川崎 章弘, 倉井 佐知, 土居 久志, 矢野 恒夫, 渡辺 恭良, 尾上 浩隆

  日本分子イメージング学会, May 2011, JSMI Report, 4(2) (2), 125 - 125, Japanese


• 六君子湯の作用解析を目的とした放射性標識グレリンの合成と基礎的検討

  西村 三恵, 長谷川 功紀, 佐古 健生, 中村 郁子, 林中 恵美, 和田 康弘, 渡辺 恭良

  (公社)日本薬学会, Mar. 2011, 日本薬学会年会要旨集, 131年会(4) (4), 151 - 151, Japanese


• 10.慢性疲労症候群患者におけるGTPシクロヒドロラーゼI遺伝子多型の解析(第425回研究協議会研究発表要旨,ビタミンB研究委員会)

  堀口 美恵子, 福田 早苗, 一瀬 宏, 中富 康仁, 山口 浩二, 倉恒 弘彦, 渡辺 恭良

  公益社団法人 日本ビタミン学会, 2011, ビタミン, 85(11) (11), 616 - 616, Japanese


• 6.疲労のメタボローム解析(第423回研究協議会研究発表要旨,ビタミンB研究委員会)

  渡辺 恭良, 片岡 洋祐, 金 光華, 山野 恵美, 倉恒 弘彦, 山口 浩二, 中富 康仁

  公益社団法人 日本ビタミン学会, 2011, ビタミン, 85(3) (3), 152 - 153, Japanese


• Analysis of nociceptive pathway in rat brain using small-animal PET

  Yilong Cui, Takeo Sako, Kaori Okuyama, Hiroshi Toyoda, Kayo Onoe, Emi Hayashinaka, Yasuhiro Wada, Yasuyoshi Watanabe, Yosky Kataoka

  2011, NEUROSCIENCE RESEARCH, 71, E81 - E81, English

  Summary international conference


• 【肝病態生理研究のあゆみ】 [¹¹C]Telmisartanを用いたPositron Emission Tomography(PET)による肝胆系輸送評価

  高島 忠之, 橋爪 良信, 土居 久志, 和田 康弘, 渡辺 恭良, 千田 道雄, 山根 登茂彦, 佐々木 將博, 清水 敬二, 岩本 明美, 景山 浩充, 前田 和哉, 楠原 洋之, 杉山 雄一

  ライフサイエンス出版(株), Dec. 2010, 薬理と治療, 38(Suppl.2) (Suppl.2), S103 - S109, Japanese


• N末端Cu結合モチーフ(ATCUN)を用いた64Cu標識法の開発

  長谷川 功紀, 西村 三恵, 林中 恵美, 和田 康弘, 片岡 洋祐, 渡辺 恭良

  (一社)日本核医学会, Sep. 2010, 核医学, 47(3) (3), 386 - 386, Japanese


• Evaluation of In Vivo Hepatobiliary Transport Using Positron Emission Tomography (PET): Studies in Rats and Application to Microdosing Clinical Studies

  Tadayuki Takashima, Hiroko Nagata, Hideki Ishii, Ryosuke Ijuin, Takahiro Nakae, Masaaki Tanaka, Yoshihito Shigihara, Suzuka Ataka, Hisashi Doi, Yasuhiro Wada, Masaaki Suzuki, Kazuya Maeda, Hiroyuki Kusuhara, Yuichi Sugiyama, Yasuyoshi Watanabe

  Aug. 2010, DRUG METABOLISM REVIEWS, 42, 311 - 311, English

  Summary international conference


• 11C-Labeled cetrozole: an excellent PET probe for aromatase in brain in emotional disorders

  高橋 佳代, 細谷 孝充, 尾上 嘉代, 土居 久志, 長田 浩子, 渡辺 由美子, 平松 俊行, Li Xiao-Le, 和田 康弘, 高島 忠之, 片山 由美子, 山中 創, 鈴木 正昭, 尾上 浩隆, 渡辺 恭良

  日本神経化学会, Aug. 2010, 神経化学, 49(2-3) (2-3), 773 - 773, English


• ヒートアイランドが疲労発生に与える影響

  宮沢和貴, 玄地裕, 井原智彦, 鳴海大典, 福田早苗, 小山英則, 渡辺恭良

  日本疲労学会, 25 Jun. 2010, 日本疲労学会誌, 6(1) (1), 84 - 84, Japanese


• 芳香物質が自律神経に与える影響について 慢性疲労症候群患者と健常者の比較

  笹部 哲也, 福田 早苗, 山口 浩二, 中富 康仁, 神楽 美香, 倉恒 弘彦, 渡辺 恭良

  日本疲労学会, Jun. 2010, 日本疲労学会誌, 6(1) (1), 103 - 103, Japanese


• 最近の知見 透析患者における栄養機能飲料摂取による抗疲労効果の検証研究

  福田 早苗, 小山 英則, 藤井 比佐子, 平山 佳伸, 木山 博資, 近藤 一博, 西澤 良記, 渡辺 恭良

  日本疲労学会, Jun. 2010, 日本疲労学会誌, 6(1) (1), 60 - 60, Japanese


• 小児慢性疲労症候群患児と健常児に共通する疲労と神経過剰賦活の関係

  水野 敬, 田中 雅彰, 鴫原 良仁, 福田 早苗, 山野 恵美, 川谷 淳子, 上土井 貴子, 友田 明美, 三池 輝久, 松村 京子, 田邊 宏樹, 定藤 規弘, 渡辺 恭良

  日本疲労学会, Jun. 2010, 日本疲労学会誌, 6(1) (1), 81 - 81, Japanese


• 末期腎不全患者における自律神経機能と疲労およびQOL

  藤井 比佐子, 小山 英則, 福田 早苗, 平山 佳伸, 渡辺 恭良, 稲葉 雅章, 西澤 良記

  日本疲労学会, Jun. 2010, 日本疲労学会誌, 6(1) (1), 86 - 86, Japanese


• N末端Cu結合モチーフ(ATCUN)を用いた64Cu標識法の開発

  長谷川 功紀, 西村 三恵, 林中 美恵, 和田 康弘, 渡辺 恭良

  日本分子イメージング学会, May 2010, JSMI Report, 3(2) (2), 105 - 105, Japanese


• 炎症モデルにおけるTGF-β活性化反応のPETイメージング

  金山 洋介, 角田 ちぬよ, 長谷川 功紀, 松本 恭子, 和田 康弘, 林中 恵美, 榎本 秀一, 原 詳子, 小嶋 聡一, 渡辺 恭良

  日本分子イメージング学会, May 2010, JSMI Report, 3(2) (2), 108 - 108, Japanese


• 【疲労と機能性食品】抗疲労食の開発

  福田 早苗, 梶本 修身, 渡辺 恭良

  (有)フジメディカル出版, Apr. 2010, Functional Food, 3(4) (4), 330 - 333, Japanese


• TGF-β活性化反応検出ELISA法による肝障害患者血漿中のLAP断片量の測定と、局所LAP断片集積のPETイメージングの試み

  桐田 暁子, 原 詳子, 松浦 知和, 斎藤 勝也, 永妻 啓介, 上竹 慎一郎, 瀬嵐 康人, 高木 一郎, 相沢 良夫, 浦島 充佳, 金山 洋介, 角田 ちぬよ, 長谷川 功紀, 渡辺 恭良, 小嶋 聡一

  (一社)日本肝臓学会, Apr. 2010, 肝臓, 51(Suppl.1) (Suppl.1), A178 - A178, Japanese


• Mapping of regional brain activation in response to fatigue-load and recovery in rats with c-Fos immunohistochemistry

  Ko-hei Akazawa, Yilong Cui, Masaaki Tanaka, Yosky Kataoka, Yukio Yoneda, Yasuyoshi Watanabe

  Apr. 2010, NEUROSCIENCE RESEARCH, 66(4) (4), 372 - 379, English, International magazine


• 膵臓癌のPET撮像を目的とした放射標識セクレチンの合成とその評価

  西村 三恵, 長谷川 功紀, 向井 英史, 中村 郁子, 佐古 健生, 林中 恵美, 和田 康弘, 渡辺 恭良

  (公社)日本薬学会, Mar. 2010, 日本薬学会年会要旨集, 130年会(4) (4), 129 - 129, Japanese


• Analysis of nociceptive pathway in a rat model of migraine using small-animal PET

  Yilong Cui, Takeo Sako, Hiroshi Toyoda, Kaori Okuyama, Kayo Onoe, Emi Hayashinaka, Yasuhiro Wada, Yasuyoshi Watanabe, Yosky Kataoka

  2010, NEUROSCIENCE RESEARCH, 68, E425 - E425, English

  [Refereed]

  Summary international conference


• 15R‐[11C]TIC‐Meを用いた薬物動態PETイメージングの有用性評価

  高島忠之, 田中雅彰, 鴫原良仁, 安宅鈴香, 伊集院良祐, 石井英樹, 和田康弘, 土居久志, 前田和哉, 杉山雄一, 渡辺恭良

  (一社)日本核医学会, 30 Sep. 2009, 核医学, 46(3) (3), S237 - 293, Japanese


• 糖尿病の予防や早期発見・治療のための膵β細胞イメージング

  佐古 健生, 長谷川 功紀, 和田 康弘, 千田 道雄, 渡辺 恭良

  (一社)日本核医学会, Sep. 2009, 核医学, 46(3) (3), 318 - 318, Japanese


• 疲労関連症状出現と心理社会的予測因子の検討 追跡調査の結果から

  山野 恵美, 福田 早苗, 水野 敬, 田中 雅彰, 片岡 洋祐, 上土井 貴子, 川谷 淳子, 高野 美雪, 友田 明美, 松村 京子, 三池 輝久, 渡辺 恭良

  日本疲労学会, May 2009, 日本疲労学会誌, 5(1) (1), 75 - 75, Japanese


• 子どもの疲労 小中学校における疲労に関するコホート研究

  福田 早苗, 山野 恵美, 渡辺 恭良

  日本疲労学会, May 2009, 日本疲労学会誌, 5(1) (1), 44 - 44, Japanese


• 基礎疾患に基づく疲労 腎不全透析患者の疲労とその介入試験の試み

  小山 英則, 福田 早苗, 渡辺 恭良, 藤井 比佐子, 平山 佳伸, 西沢 良記

  日本疲労学会, May 2009, 日本疲労学会誌, 5(1) (1), 33 - 33, Japanese


• 血中fetuin-A濃度と血管内皮機能との関連性

  川野 直也, 森 克仁, 絵本 正憲, 小山 英則, 菊川 友子, 藤井 比佐子, 福田 早苗, 東海 秀吉, 平山 佳伸, 渡辺 恭良, 西沢 良記

  (一社)日本糖尿病学会, Apr. 2009, 糖尿病, 52(Suppl.1) (Suppl.1), S - 258, Japanese


• PET技術を利用した消化管インスリン吸収の分子イメージング解析

  亀井 敬泰, 森下 真莉子, 高山 幸三, 金山 洋介, 長谷川 功紀, 西村 三恵, 和田 康弘, 渡辺 恭良

  (公社)日本薬学会, Mar. 2009, 日本薬学会年会要旨集, 129年会(4) (4), 285 - 285, Japanese


• CENTRAL CHANGES IN EXPERIMENTAL GLAUCOMA

  Kazuyuki Imamura, Hirotaka Onoe, Masamitsu Shimazawa, Satoshi Nozaki, Hiroshi Mizuma, Yasuhiro Wada, Kayo Onoe, Kiyoshi Ishii, Chihiro Mayama, Takazumi Taniguchi, Masaaki Sasaoka, Hajime Yamanaka, Hideaki Hara, Shigeru Tanaka, Makoto Araie, Yasuyoshi Watanabe

  2009, JOURNAL OF PHYSIOLOGICAL SCIENCES, 59, 524 - 524, English

  Summary international conference


• Mapping serotonin transporters with [C-11]DASB positron emission tomography in common marmosets under conscious condition: comparison with macaque monkeys

  Chihiro Yokoyama, Hajime Yamanaka, Kayo Onoe, Akihiro Kawasaki, Hiroko Nagata, Keiko Shirakami, Hisashi Doi, Yasuyoshi Watanabe, Hirotaka Onoe

  2009, Neuroscience Research, 65, S227 - S227, English

  Summary international conference


• Evaluation of pathophysiological features of migraine using micro PET

  Yilong Cui, Tadayuki Takashima, Kayo Onoe, Miho Shukuri, Misato Takashima-Hirano, Takeo Sako, Emi Hayashinaka, Yasuhiro Wada, Hisashi Doi, Hirotaka Onoe, Yasuyoshi Watanabe, Yosky Kataoka

  2009, NEUROSCIENCE RESEARCH, 65, S258 - S258, English

  Summary international conference


• NEURAL AND MOLECULAR MECHANISMS OF CENTRAL FATIGUE IN THE ANIMAL MODELS

  Yilong Cui, Yasuyoshi Watanabe, Yosky Kataoka

  2009, JOURNAL OF PHYSIOLOGICAL SCIENCES, 59, 107 - 107, English

  [Refereed]

  Summary international conference


• 芳香療法に使用される香気吸入時の心拍変動について

  笹部 哲也, 福田 早苗, 山野 恵美, 山口 浩二, 渡辺 恭良, 古郷 幹彦

  (一社)日本歯科心身医学会, Dec. 2008, 日本歯科心身医学会雑誌, 23(1-2) (1-2), 73 - 73, Japanese


• ストロボ光刺激の時間周波数が視覚誘発脳磁場に与える影響

  鴫原 良仁, 田中 雅彰, 露口 尚弘, 渡辺 恭良

  (一社)日本臨床神経生理学会, Oct. 2008, 臨床神経生理学, 36(5) (5), 538 - 538, Japanese


• 香りの抗疲労作用に関する生理心理学的研究

  福田 早苗, 渡辺 恭良

  (公社)日本心理学会, Jul. 2008, 日本心理学会大会発表論文集, 72回, 1059 - 1059, Japanese


• 疲労時の神経-免疫-内分泌相互作用系の低下:中枢神経系の過剰活性化後の疲労と睡眠の誘導(Deterioration of neuro-immuno-endocrine interaction in fatigue: Fatigue and sleep induction following excessive activation of the central nervous system)

  Kataoka Yosky, Cui Yilong, Tamura Yasuhisa, Yamato Masanori, Jin Guanghua, Watanabe Yasuyoshi

  (一社)日本生理学会, Apr. 2008, The Journal of Physiological Sciences, 58(Suppl.) (Suppl.), S18 - S18, English


• 疲労の分子神経メカニズム 質問紙に見る慢性疲労病態の特徴

  福田 早苗, 渡辺 恭良

  日本疲労学会, Feb. 2008, 日本疲労学会誌, 4(1) (1), 47 - 47, Japanese


• 疲労と食生活、栄養素との関連

  藤井 比佐子, 福田 早苗, 渡辺 恭良, 小山 英則, 西沢 良記, 塚田 定信, 古澤 美香, 平山 佳伸

  日本疲労学会, Feb. 2008, 日本疲労学会誌, 4(1) (1), 68 - 68, Japanese


• 小中学生の意欲・疲労と学習効率に関するコホート研究 気質・性格と疲労の関連性の時系列的検討

  山野 恵美, 福田 早苗, 水野 敬, 田中 雅彰, 上土井 貴子, 川谷 淳子, 友田 明美, 松村 京子, 三池 輝久, 渡辺 恭良

  日本疲労学会, Feb. 2008, 日本疲労学会誌, 4(1) (1), 67 - 67, Japanese


• 疲労の評価法 疲労の生物学的評価法から見えてきた疲労の分子メカニズム

  近藤 一博, 小林 伸行, 清水 昭宏, 倉恒 弘彦, 渡辺 恭良

  日本疲労学会, Feb. 2008, 日本疲労学会誌, 4(1) (1), 56 - 56, Japanese


• Fatigue science for human health

  Yasuyoshi Watanabe, Birgitta Evengård, Benjamin H. Natelson, Leonard A. Jason, Hirohiko Kuratsune

  Springer Japan, 2008, Fatigue Science for Human Health, 1 - 236, English

  Others


• Chronic fatigue syndrome

  Hirohiko Kuratsune, Yasuyoshi Watanabe

  Springer Japan, 2008, Fatigue Science for Human Health, 67 - 88, English


• PET imaging of microglia activation with [C-11]PK11195 in the rat model of migraine

  Yilong Cui, Tadayuki Takashima, Yasuhisa Tamura, Yasuhiro Wada, Hisashi Doi, Misato H. Takashima, Hiroko Nagata, Yosky Kataoka, Yasuyoshi Watanabe

  2008, NEUROSCIENCE RESEARCH, 61, S210 - S210, English

  Summary international conference


• 老齢ラット大脳皮質におけるNG2陽性細胞の領域特異的な変化について(Region-specific degeneration of NG2+ cells in the cerebral cortex of aged rats)

  Tamura Yasuhisa, Cui Yilong, Watanabe Yasuyoshi, Kataoka Yosky

  日本神経化学会, Aug. 2007, 神経化学, 46(2-3) (2-3), 518 - 518, English


• Micro PETを用いた片頭痛病態モデルラットの評価(Evaluation of pathophysiological features of migraine by micro PET study using rats)

  Cui Yilong, Wada Yasuhiro, Yamato Masanori, Tamura Yasuhisa, Kataoka Yosky, Watanabe Yasuyoshi

  日本神経化学会, Aug. 2007, 神経化学, 46(2-3) (2-3), 564 - 564, English


• 実験的疲労モデルを用いた精神神経内分泌学的検討

  福田 早苗, 渡辺 恭良

  日本生理心理学会, Aug. 2007, 生理心理学と精神生理学, 25(2) (2), 129 - 129, Japanese


• 小学中学生における学習意欲、疲労と生活習慣に関する学校コホート研究

  福田 早苗, 渡辺 恭良

  (公社)日本心理学会, Jul. 2007, 日本心理学会大会発表論文集, 71回, 1125 - 1125, Japanese


• 慢性疲労症候群患者における精神障害のcomorbidityについて

  松井 徳造, 切池 信夫, 福田 早苗, 田島 成貴, 倉恒 弘彦, 西沢 良記, 渡辺 恭良

  (株)医学書院, Jun. 2007, 精神医学, 49(6) (6), 591 - 597, Japanese


• CFSの診断基準と関係する精神障害、特に気分変調性障害・身体表現性障害について

  松井 徳造, 切池 信夫, 倉恒 弘彦, 福田 早苗, 田島 成貴, 松田 泰範, 片岡 浩平, 西沢 良記, 渡辺 恭良

  日本疲労学会, Jun. 2007, 日本疲労学会誌, 3(1) (1), 72 - 72, Japanese


• 慢性腎不全透析患者の疲労の実態

  小山 英則, 福田 早苗, 庄司 哲雄, 田畑 勉, 奥野 仙二, 岡村 幹夫, 岡田 茂樹, 倉恒 弘彦, 渡辺 恭良, 西沢 良記

  日本疲労学会, Jun. 2007, 日本疲労学会誌, 3(1) (1), 84 - 84, Japanese


• 小中学生の意欲・疲労と学習効率に関するコホート研究 気質・性格と疲労の関連性の検討

  山野 恵美, 福田 早苗, 水野 敬, 田中 雅彰, 吉田 かおる, 上土井 貴子, 川谷 淳子, 友田 明美, 松村 京子, 三池 輝久, 渡辺 恭良

  日本疲労学会, Jun. 2007, 日本疲労学会誌, 3(1) (1), 76 - 76, Japanese


• 新たな疲労/疲労感の評価法 可視-近赤外スペクトルを用いた慢性疲労症候群(CFS)診断法開発

  作道 章一, 倉恒 弘彦, 小林 孝徳, 計屋 由紀子, 田島 世貴, 山口 浩二, 渡辺 恭良, 生田 和良

  日本疲労学会, Jun. 2007, 日本疲労学会誌, 3(1) (1), 65 - 65, Japanese


• 慢性腎不全血液透析患者の疲労度実態調査

  小山 英則, 庄司 哲雄, 高島 昇子, 福田 早苗, 田畑 勉, 奥野 仙二, 岡村 幹夫, 岡田 茂樹, 倉恒 弘彦, 渡辺 恭良, 西沢 良記

  (一社)日本透析医学会, May 2007, 日本透析医学会雑誌, 40(Suppl.1) (Suppl.1), 563 - 563, Japanese


• Accumulated fatigue induces over-activation and subsequent degeneration of melanotrophs in rat pituitary gland

  Tokiko Ogawa, Hiroyuki Konishi, Masaaki Tanaka, Sumiko Kiryu-Seo, Saya Nakagomi, Yasuyoshi Watanabe, Hiroshi Kiyama

  2007, NEUROSCIENCE RESEARCH, 58, S222 - S222, English

  Summary international conference


• Region-specific degeneration of NG2+cells in the cerebral cortex of aged rats

  Yasuhisa Tamura, Yilong Cui, Yasuyoshi Watanabe, Yosky Kataoka

  2007, NEUROSCIENCE RESEARCH, 58, S144 - S144, English

  [Refereed]

  Summary international conference


• [C-11]Pittsburgh Compound-B(PIB)PETによる軽度認知機能障害(MCI)の脳内アミロイドイメージング

  川村 悦史, 河邉 讓治, 林 健博, 麻植 愛, 東山 滋明, 黒岡 浩子, 鳥居 顯二, 和田 康弘, 渡辺 恭良, 塩見 進

  (一社)日本核医学会, Oct. 2006, 核医学, 43(3) (3), 266 - 266, Japanese


• ラットの長期頭蓋内自己-刺激におけるアラキドン酸カスケードの関与(Involvement of arachidonic acid cascade in long-term intracranial self-stimulation in rats)

  Cui Yilong, Kataoka Yosky, Tamura Yasuhisa, Watanabe Yasuyoshi, Yamada Hisao

  Jul. 2006, Neuroscience Research, 55(Suppl.1) (Suppl.1), S94 - S94, English

  Summary international conference


• 身体的・精神的ストレスと疲労 実験負荷と質問票の両面からの急性疲労とストレスメカニズムの検討

  福田 早苗, 田中 雅彰, 水野 敬, 田島 世貴, 渡辺 恭良

  日本疲労学会, Jul. 2006, 日本疲労学会誌, 2(1) (1), 32 - 32, Japanese


• 疲労の定量とメカニズム 疲労および意欲の脳神経メカニズムについての検討

  田中 雅彰, 水野 敬, 福田 早苗, 田島 世貴, 定藤 規弘, 渡辺 恭良

  日本疲労学会, Jul. 2006, 日本疲労学会誌, 2(1) (1), 48 - 48, Japanese


• 精神科・慢性疲労外来の受診患者の動向

  松井 徳造, 切池 信夫, 福田 早苗, 倉恒 弘彦, 田島 世貴, 渡辺 恭良, 西沢 良記

  日本疲労学会, Jul. 2006, 日本疲労学会誌, 2(1) (1), 106 - 106, Japanese


• 慢性疲労症候群(CFS)患者における気質・性格評価 Temperament and Character Inventoryを用いた検討

  福田 早苗, 倉恒 弘彦, 高島 昇子, 田島 世貴, 山口 浩二, 渡辺 恭良, 西沢 良記

  日本疲労学会, Jul. 2006, 日本疲労学会誌, 2(1) (1), 108 - 108, Japanese


• 病的疲労と慢性疲労 慢性疲労症候群(CFS)患者における疲労関連質問票64項目の適応について

  高島 昇子, 倉恒 弘彦, 福田 早苗, 田島 世貴, 山口 浩二, 岩瀬 真生, 渡辺 恭良, 西沢 良記

  日本疲労学会, Jul. 2006, 日本疲労学会誌, 2(1) (1), 66 - 66, Japanese


• 疲労のバイオマーカー 新しい慢性疲労症候群(CFS)診断法開発 CFS患者血清の可視-近赤外スペクトル多変量解析

  作道 章一, 倉恒 弘彦, 小林 孝徳, 田島 世貴, 渡辺 恭良, 生田 和良

  日本疲労学会, Jul. 2006, 日本疲労学会誌, 2(1) (1), 24 - 24, Japanese


• Chronic fatigue syndrome and stress events

  Hirohiko Kuratsune, Hirohiko Kuratsune, Hirohiko Kuratsune, Akira Shimizu, Yasuyoshi Watanabe

  01 Jan. 2006, Biotherapy, 20, 1 - 11


• Brain science on chronic fatigue

  Yasuyoshi Watanabe, Hirohiko Kuratsune, Hirohiko Kuratsune

  01 Jan. 2006, Japan Medical Association Journal, 49, 19 - 26


• 四塩化炭素誘導肝硬変ラットにおける[18F]FDGを用いた疲労時の脳糖代謝変動の検討

  横屋 史彦, 河邉 譲治, 川村 悦史, 塩見 進, 水間 広, 渡邉 恭良

  (一社)日本核医学会, Dec. 2005, 核医学, 42(4) (4), 441 - 441, Japanese


• 四塩化炭素誘導肝硬変ラットにおける[F-18]FDGを用いた疲労時の脳糖代謝変動の検討

  横屋 史彦, 河邊 譲治, 川村 悦史, 塩見 進, 水間 広, 渡辺 恭良

  (一社)日本核医学会, Sep. 2005, 核医学, 42(3) (3), 304 - 304, Japanese


• 2. 慢性疲労症候群の遺伝子発現解析(第400回ビタミンB研究委員会研究発表要旨)

  渡辺 恭良, 油谷 浩幸, 山口 浩二, 倉恒 弘彦

  公益社団法人 日本ビタミン学会, 2005, ビタミン, 79(7) (7), 352 - 353, Japanese


• Rapid methylation on carbon frameworks leading to the synthesis of a PET tracer capable of imaging a novel CNS-type prostacyclin receptor in living human brain

  M Suzuki, H Doi, T Hosoya, B Langstrom, Y Watanabe

  Sep. 2004, TRAC-TRENDS IN ANALYTICAL CHEMISTRY, 23(8) (8), 595 - 607, English


• 精神作業疲労により惹起される血液中アミノ酸レベルの変化(Changes in amino acids levels caused by mental fatigue)

  水野 敬, 野崎 聡, 山口 浩二, 水間 広, 田中 雅彰, 笹部 哲也, 杉野 友啓, 乾 富士男, 白井 智子, 須賀 裕子, 梶本 佳孝, 梶本 修身, 倉恒 弘彦, 渡辺 恭良

  日本神経化学会, Aug. 2004, 神経化学, 43(2-3) (2-3), 513 - 513, English


• ラットにおける長期間頭蓋内自己刺激における自己刺激の抑制期間及びセロトニン作動性神経系の関与(Inhibition period of self-stimulation and the involvement of the serotonergic nervous system in long-term intracranial self-stimulation in rats)

  Cui Yilong, Kataoka Yosky, Li Qing-Hua, Nozaki Satoshi, Mizuma Hiroshi, Watanabe Yasuyoshi, Yamada Hisao

  (一社)日本生理学会, Jun. 2004, The Japanese Journal of Physiology, 54(Suppl.) (Suppl.), S209 - S209, English


• In Vivo Molecular Imaging by Positron Emission Tomography(PET) and its Application to Drug Design and Diagnosis

  SUZUKI Masaaki, DOI Hisashi, HOSOYA Takamitsu, WATANABE Yasuyoshi

  Positron emission tomography (PET) is a powerful noninvasive method for molecular imaging in living systems, including the brain, heart, and other active tissues and organs. The need to develop new PET tracers has grown with the increase in use of this technique in biochemistry, medicine (diagnosis), and drug development. We here describe the overview of the recent advances and perspective in this interdisciplinary scientific area, focusing on current PET technology and new tracer synthesis particularly based on new methodologies for incorporating a short-lived ^<11>C-nuclide into bioactive organic molecules through Pd (O)-mediated rapid methylation and carbonylations. The former method has been applied to the synthesis of 15R-[^<11>C] TIC methyl ester, an efficient PET tracer for imaging a novel CNS-type prostacyclin receptor (IP_2) in living human brain.

  The Biophysical Society of Japan General Incorporated Association, 2004, Biophysics, 44(6) (6), 265 - 270, Japanese


• 大脳皮質の過剰興奮モデルにおける脳実質と髄膜の機能的関係(Functional relationship between brain parenchyma and meninges in an excessive excitation model of the cerebral cortex)

  Yamada Hisao, Kataoka Yosky, Cui Yilong, Tamura Yasuhisa, Osawa Manabu, Koumoto Ryousuke, Yonemura Takuma, Watanabe Yasuyoshi

  エルゼビア・ジャパン(株), May 2003, Neuroscience Research, (Suppl.26) (Suppl.26), S93 - S93, English


• A NEurite outgrowth-promoting prostaglandin that may enhance higher neuronal functions

  T Satoh, K Furuta, M Suzuki, Y Watanabe

  2002, JAPANESE JOURNAL OF PHARMACOLOGY, 88, 92P - 92P, English

  Summary international conference


• Specific ligand for a central type prostacyclin receptor attenuates neuronal damage in a rat model of focal cerebral ischemia

  H Takamatsu, H Tsukada, Y Watanabe, YL Cui, Y Kataoka, T Hosoya, M Suzuki, Y Watanabe

  Jan. 2002, BRAIN RESEARCH, 925(2) (2), 176 - 182, English, International magazine


• 刺激依存性・海馬歯状回特異的新規ホスホリパーゼA2(KIDScPLA2)の酵素学的性質の検討

  白川 純, 岸本 幸治, 魚住 尚紀, 和泉 孝志, 黒柳 秀人, 鈴木 陽一, 白澤 卓二, 中舘 和彦, 渡辺 恭良, 清水 孝雄

  (公社)日本生化学会, Aug. 2001, 生化学, 73(8) (8), 845 - 845, Japanese


• Changes in mACh, NMDA and GABA(A) receptor binding after lateral fluid-percussion injury: in vitro autoradiography of rat brain frozen sections

  S Sihver, N Marklund, L Hillered, B Langstrom, Y Watanabe, M Bergstrom

  Aug. 2001, JOURNAL OF NEUROCHEMISTRY, 78(3) (3), 417 - 423, English


• Middle cerebral artery occlusion and reperfusion in primates monitored microdialysis and sequential positron emission tomography

  P Enblad, P Frykholm, J Valtysson, HCS Silander, J Andersson, KJ Fasth, Y Watanabe, B Langstrom, L Hillered, L Persson

  Jul. 2001, STROKE, 32(7) (7), 1574 - 1580, English


• Effects of monocular deprivation on the expression pattern of alpha-1 and beta-1 adrenergic receptors in the kitten visual cortex.

  K Nakadate, K Imamura, Y Watanabe

  Jun. 2001, Neuroscience research, 40(2) (2), 155 - 62, English, International magazine

  [Refereed]


• Coexpression of microsomal-type prostaglandin E synthase with cyclooxygenase-2 in brain endothelial cells of rats during endotoxin-induced fever

  K Yamagata, K Matsumura, W Inoue, T Shiraki, K Suzuki, S Yasuda, H Sugiura, CY Cao, Y Watanabe, S Kobayashi

  Apr. 2001, JOURNAL OF NEUROSCIENCE, 21(8) (8), 2669 - 2677, English


• 巣状脳虚血のラットモデルにおける中枢型プロスタサイクリン受容体リガンドの神経保護作用(Neuroprotective effect of a central type prostacyclin receptor ligand in a rat model of focal cerebral ischemia)

  Takamatsu Hiroyuki, Tsukada Hideo, Kataoka Yosky, Cui Yilong, Watanabe Yumiko, Hosoya Takamitsu, Suzuki Masaaki, Watanabe Yasuyoshi

  (公社)日本薬理学会, Mar. 2001, The Japanese Journal of Pharmacology, 85(Suppl.I) (Suppl.I), 233P - 233P, English


• N-(2-Chloroethyl)-N-ethyl-2-bromobenzylamine reduces intracellular calcium response to noradrenaline in rat visual cortex.

  M Yamamoto, K Imamura, M Kobayashi, K Nakadate, C Yokoyama, Y Watanabe, M Yamamoto, A Negi

  2001, Neuroscience, 107(2) (2), 209 - 18, English, International magazine

  [Refereed]


• 生後発達に伴うセロトニン受容体2Aと2Cの発現パターンの変化

  李慶華, 中舘和彦, 田中(中舘)佐和子, 中塚大策, 野崎聡, さい翼龍, 渡辺恭良

  2001, 日本神経科学大会プログラム・抄録集, 24th


• Cyclopentenone prostaglandin derivatives as novel neurotrophic compounds for CNS neurons.

  2001, J. Neurochem., 77, 55 - 62


• Cortical networks recruited for time perception: A monkey positron emission tomography (PET) study

  H Onoe, M Komori, K Onoe, H Takechi, H Tsukada, Y Watanabe

  Jan. 2001, NEUROIMAGE, 13(1) (1), 37 - 45, English


• 新プロスタサイクリン受容体により活性化される神経防御薬の開発(Development of neuroprotective drug active through a novel prostacyclin receptor)

  Watanabe Yumiko, Cui Yilong, Satoh Takumi, Kataoka Yosky, Nakatsuka Daisaku, Takamatsu Hiroyuki, Tsukada Hideo, Suzuki Masaaki, Watanabe Yasuyoshi

  エルゼビア・ジャパン(株), Dec. 2000, Neuroscience Research, (Suppl.24) (Suppl.24), S10 - S10, English


• Control of neurotransmission, behaviour and development, by photo-dynamic manipulation of tissue redox state of brain targets

  Y Kataoka, H Morii, K Imamura, Y Cui, M Kobayashi, Y Watanabe

  Dec. 2000, EUROPEAN JOURNAL OF NEUROSCIENCE, 12(12) (12), 4417 - 4423, English


• Facilitatory roles of novel compounds designed from cyclopentenone prostaglandins on neurite outgrowth-promoting activities of nerve growth factor

  T Satoh, K Furuta, K Tomokiyo, D Nakatsuka, M Tanikawa, M Nakanishi, M Miura, S Tanaka, T Koike, H Hatanaka, K Ikuta, M Suzuki, Y Watanabe

  Sep. 2000, JOURNAL OF NEUROCHEMISTRY, 75(3) (3), 1092 - 1102, English


• 脂質メディエーター研究の最前線 刺激依存性・海馬歯状回特異的新規ホスホリパーゼA2アイソフォーム

  岸本 幸治, 魚住 尚紀, 和泉 孝志, 清水 孝雄, 黒柳 秀人, 鈴木 陽一, 白澤 卓二, 中舘 和彦, 渡辺 恭良

  (公社)日本生化学会, Aug. 2000, 生化学, 72(8) (8), 607 - 607, Japanese


• Pterinergic Neurons?

  渡辺 恭良, 田中 佐和子[中舘], 中舘 和彦, 今村 一之

  (公社)日本ビタミン学会, Jun. 2000, ビタミン, 74(5〜6) (5〜6), 329 - 329, Japanese


• Developmental regulation of intracellular calcium response to noradrenaline and NMDA in primary visual cortex

  M Yamamoto, S Komai, M Kobayashi, K Imamura, Y Watanabe

  Mar. 2000, INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 41(4) (4), S565 - S565, English

  Summary international conference


• Linear and nonlinear interactions between horizontal and vertical inputs to pyramidal cells in the superficial layers of the cat visual cortex.

  2000, J. Neurosci., 20, 1931 - 1940


• Selective suppression of horizontal propagation in rat visual cortex by norepinephrine

  M Kobayashi, K Imamura, T Sugai, N Onoda, M Yamamoto, S Komai, Y Watanabe

  Jan. 2000, EUROPEAN JOURNAL OF NEUROSCIENCE, 12(1) (1), 264 - 272, English


• 刺激依存性・時期特異的・脳特異的新規ホスホリパーゼA2

  岸本 幸治, 尾崎 仁士, 中舘 和彦, 許 麗華, 黒柳 秀人, 鈴木 陽一, 白澤 卓二, 渡辺 恭良

  (公社)日本生化学会, Aug. 1999, 生化学, 71(8) (8), 976 - 976, Japanese


• PET・fMRIを用いた嗅覚系の解析

  渡辺 恭良, 今村 一之, 小林 真之, 片岡 洋祐, 尾上 浩隆, 中舘 和彦, 駒井 章治, 吉久保 真一, 服部 慶明, 永井 康雄, 澤田 徹

  15 Apr. 1999, 日本鼻科学会会誌, 38(1) (1), 149 - 149, Japanese


• GTP Cyclohydrolase Iとモノアミン生合成系の初期発達

  渡辺 恭良, 六車 恵子, 田中 佐和子, 中舘 和彦

  (公社)日本ビタミン学会, Mar. 1999, ビタミン, 73(3) (3), 224 - 225, Japanese


• 眼優位可塑性:c-Fos発現による可塑性評価と修飾系の関与

  今村 一之, 中舘 和彦, 渡辺 恭良

  (一社)日本生理学会, Jan. 1999, 日本生理学雑誌, 61(1) (1), 57 - 57, Japanese


• Characterization of plasticity relating molecules in mammalian visual cortex by combining dark rearing and subtractive cDNA techniques.

  PA Kaub, K Imamura, Y Watanabe

  1999, JOURNAL OF NEUROCHEMISTRY, 73, S96 - S96, English

  Summary international conference


• Electron microscopic evidence for induction of cyclooxygenase-2 in brain endothelial cells.

  K Matsumura, C Cao, M Ozaki, H Morii, K Nakadate, Y Watanabe

  29 Sep. 1998, Annals of the New York Academy of Sciences, 856, 278 - 80, English, International magazine

  [Refereed]


• 生体アミンによる眼優位可塑性の調節 ラット視覚野におけるc-FOS免疫組織化学による検討

  中舘 和彦, 今村 一之, 小林 真之, Kaub Peter, 渡辺 恭良

  日本神経化学会, Sep. 1998, 神経化学, 37(3) (3), 527 - 527, Japanese


• Brain endothelial cells express cyclooxygenase-2 during lipopolysaccharide-induced fever: light and electron microscopic immunocytochemical studies.

  K Matsumura, C Cao, M Ozaki, H Morii, K Nakadate, Y Watanabe

  15 Aug. 1998, The Journal of neuroscience : the official journal of the Society for Neuroscience, 18(16) (16), 6279 - 89, English, International magazine

  [Refereed]


• Is parvalbumin immunoreactivity in the rat visual cortex a reliable neuronal marker for the effect of monocular deprivation?

  Y Hada, Y Yamada, M Yamamoto, K Muguruma, T Shiomitsu, N Mataga, K Imamura, Y Watanabe

  Mar. 1997, INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 38(4) (4), 2900 - 2900, English

  Summary international conference


• Differential expression of immediate early genes, c-fos and ZIF268 in the visual cortex of young rats: Effect of DSP4 on their expression.

  Y Yamada, Y Hada, M Yamamoto, N Mataga, T Shiomitsu, K Imamura, Y Watanabe

  Mar. 1997, INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 38(4) (4), 2897 - 2897, English

  Summary international conference


• Synthesis of O-[11c]acetyl CoA, 11[C]acetyl-L-carnitine, and L- [11C]carnitine labelled in specific positions, applied in pet studies on rhesus monkey

  Gunilla B. Jacobson, Yasuyoshi Watanabe, Sven Valind, Hirohiko Kuratsune, Bengt Långström

  Elsevier Inc., 1997, Nuclear Medicine and Biology, 24(5) (5), 471 - 478, English


• 中枢神経型プロスタサイクリン受容体IP2の局在と性質

  渡辺 由美子, 松村 潔, 森井 博史, 武地 一, 加藤 孝一, 福永 広文, 野依 良治, 細谷 孝充, 竹内 恭子, 鈴木 正昭, 渡辺 恭良

  01 Aug. 1996, 日本分子生物学会年会プログラム・講演要旨集, 19, 514, Japanese


• KETAMINE INCREASES THE STRIATAL N-[C-11]METHYLSPIPERONE BINDING IN-VIVO - POSITRON EMISSION TOMOGRAPHY STUDY USING CONSCIOUS RHESUS-MONKEY

  H ONOE, O INOUE, K SUZUKI, H TSUKADA, T ITOH, N MATAGA, Y WATANABE

  Nov. 1994, BRAIN RESEARCH, 663(2) (2), 191 - 198, English