Updated on 2024/07/13

写真a

 
MURAKAMI Yoshihiro
 
Organization
Brain Research Institute Center for Integrated Human Brain Science Associate Professor
Title
Associate Professor
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Degree

  • 博士(材料科学) ( 2004.9   北陸先端科学技術大学院大学 )

  • 学士(農学) ( 1998.3   名古屋大学 )

  • 修士(農学) ( 1990.3   名古屋大学 )

Research Areas

  • Life Science / Bioorganic chemistry  / PET, 有機合成

Research History (researchmap)

  • Niigata University   Brain Research Institute Center for Integrated Human Brain Science Department of Functional Neurology and Neurosurgery   Associate Professor

    2022.1

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    Country:Japan

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  • アステラス製薬株式会社

    1990.4 - 2021.12

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    Country:Japan

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Research History

  • Niigata University   Center for Integrated Human Brain Science, Brain Research Institute   Associate Professor

    2022.1

Education

  • Japan Advanced Institute of Science and Technology   材料科学研究科   機能科学専攻

    2002.4 - 2004.9

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    Country: Japan

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  • Nagoya University   Graduate School of Bioagricultural Sciences   農芸化学科

    1988.4 - 1990.3

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    Country: Japan

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  • Nagoya University   School of Agricultural Sciences   農芸化学科

    1984.4 - 1988.3

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    Country: Japan

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Professional Memberships

  • Society of Nuclear Medicine and Molecular Imaging

    2003.5

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  • 日本核医学会

    2003.5

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Qualification acquired

  • Chief Person of Radiation Handling (first and second kind)

 

Papers

  • Corticobasal syndrome mimicking Foix-Chavany-Marie syndrome with suggested 4-repeat tauopathy by tau PET. International journal

    Kosei Nakamura, Yasuko Kuroha, Masahiro Hatakeyama, Atsushi Michael Kimura, Yukimi Nakamura, Yoshihiro Murakami, Masaki Watanabe, Hironaka Igarashi, Tetsuya Takahashi, Hitoshi Shimada

    BMC geriatrics   23 ( 1 )   838 - 838   2023.12

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    BACKGROUND: Corticobasal syndrome (CBS) is a neurodegenerative disease diagnosed based on clinical manifestations such as asymmetrical parkinsonism, limb apraxia, and speech and language impairment. The background pathology of CBS is commonly a variety of proteinopathies, but association with cerebrovascular disease has also been reported. Foix-Chavany-Marie syndrome (FCMS) is a rare neurological disorder characterized by facio-pharyngo-glossal diplegia with automatic-voluntary movement dissociation presenting with bilateral paresis of the facial, lingual, pharyngeal and masticatory muscles. FCMS is commonly attributable to stroke. Transactive response DNA binding protein of 43 kD (TDP-43) proteinopathy is also known as the pathological background of FCMS, while the pathological background of the majority of CBS cases consists of diverse tauopathies instead of TDP-43 proteinopathy. In this report, we describe a case mimicking FCMS that was finally diagnosed as CBS with suggested 4-repeat tauopathy. CASE PRESENTATION: A 68-year-old female started experiencing difficulty speaking followed by difficulty writing, and especially texting, several years before her visit. Her impairment had been gradually worsening, and she came to our hospital. On neurological examination, she demonstrated the facial apraxia, frontal lobe dysfunction, and upper motor neuron signs. She presented some characteristics suggestive of FCMS. Her symptoms exhibited rapid progression and myoclonus, parkinsonism, and left-side dominant cortical sensory deficit occurred, resulting in the fulfillment of diagnostic criteria for CBS after 9 months. Tau PET imaging displayed notable ligand uptake in the brainstem, subthalamic nuclei, basal ganglia, and bilateral subcortical frontal lobe, suggesting that her pathological background was 4-repeat tauopathy. As a result of her progressive dysphagia, she became unable to eat and passed away after 12 months. CONCLUSION: We hereby present an atypical case of CBS showing clinical features mimicking FCMS at first presentation. TDP-43 proteinopathy was suspected based on the clinical symptoms in the early stages of the disease; however, the clinical course and imaging findings including tau PET suggested that her pathological background was 4-repeat tauopathy.

    DOI: 10.1186/s12877-023-04564-z

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  • Synthesis and Preliminary Evaluation of an 18F-labeled Oleate Analog to Image Fatty Acid Beta-Oxidation in the Absence of Metabolic Defluorination. International journal

    Yoshihiro Murakami, Yuji Fujita, Hiroshi Fushiki

    Molecular imaging and biology   25 ( 3 )   495 - 502   2023.6

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    PURPOSE: Fatty acid oxidation (FAO) is a key parameter for evaluating cardiovascular, oncologic, neurologic, and other metabolic diseases. Several single-photon emission computed tomography and positron emission tomography (PET) tracers have been developed to measure FAO. Among these, 18-[18F]fluoro-4-thia-oleate ([18F]FTO), first developed by DeGrado et al., is well characterized. Here, we synthesized several analogs of [18F]FTO to improve the metabolic stability of the C-18F bond, and preliminarily evaluated their performance in monkey PET studies. PROCEDURES: Several secondary 18F-fluorinated analogs, 17-[18F]fluoro-4-thia-oleate (17-[18F]FTO), 15-[18F]fluoro-4-thia-oleate (15-[18F]FTO), 12-[18F]fluoro-4-thia-oleate (12-[18F]FTO), 7-[18F]fluoro-4-thia-oleate, (7-[18F]FTO, [18F]AS3504073-00), and 6-[18F]fluoro-4-thia-oleate (6-[18F]FTO), were synthesized from tosylate or bromide precursors using similar procedures. Nucleophilic 18F fluorination on each precursor was performed using [18F]tetrabutylammonium fluoride/tetrabutylammonium hydrocarbonate, followed by hydrolysis of methylester. All synthesized 18F-labeled compounds were administered to cynomolgus monkeys, and PET measurements were performed. From the monkey PET studies, 7-[18F]FTO was selected as the best tracer and used to perform preliminary evaluations in mice. RESULTS: All five compounds had sufficient quality and stability for animal experiments. In monkey PET studies, 12-, 7-, and 6-[18F]FTO showed greater accumulation in the heart than [18F]FTO, but not 17- and 15-[18F]FTO. Only 7-[18F]FTO did not show significant accumulation in the bone. The standardized uptake values (SUVs) for 12-[18F]FTO, 7-[18F]FTO, and 6-[18F]FTO were 9.77, 9.26, and 7.25 in the heart, and 3.17, n.d., and 1.96 in the bone 1 h after administration, respectively. In mouse distribution studies, SUVs 1 h after administration of 7-[18F]FTO and [18F]FTO were 10.4 and 10.0 in the heart, and 0.37 and 3.48 in the femur, respectively. Administration of etomoxir, a carnitine palmitoyltransferase inhibitor, reduced SUVs of 7-[18F]FTO and [18F]FTO in the heart by 91% and 87%, respectively. CONCLUSIONS: We developed a novel PET tracer 7-[18F]FTO/[18F]AS3504073-00 for FAO imaging. 7-[18F]FTO had an excellent PET tracer profile, suggesting it may be a useful tracer for FAO imaging. Further evaluations of the tracer are ongoing.

    DOI: 10.1007/s11307-022-01777-3

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  • Predicting response to sepantronium bromide (YM155), a survivin suppressant, by PET imaging with [C-11]YM155

    Keisuke Mitsuoka, Aya Kita, Yoshihiro Murakami, Kenna Shirasuna, Akihiro Noda, Kentaro Yamanaka, Naoki Kaneko, Sosuke Miyoshi

    NUCLEAR MEDICINE AND BIOLOGY   64-65   41 - 46   2018.9

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    Introduction: Sepantronium bromide (YM155) is a survivin suppressant that induces apoptosis in tumor cells. Although YM155 induces tumor regression in various tumor types in vivo, phase I and II studies demonstrated responding and non-responding patient populations. We investigated C-11-labeled YM155 ([C-11]YM155) used as a positron emission tomography (PET) tracer to assess whether tumor uptake of [C-11]YM155 correlated with its anti-tumor effect, thereby allowing identification of patients who would respond to YM155 treatment.Methods: (1) Uptake of YM155 was measured in 39 human cancer cell lines in vitro using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). (2) In vivo tumor uptake was assessed in xenografted mice and total body distribution was evaluated in a cynomolgus monkey using [C-11]YM155 with PET/computed tomography (Cr) (mice) and PET (monkey) imaging.Results: Intracellular uptake of YM155 in human cancer cell lines correlated well with its in vitro efficacy measured by GI(50) (Pearson's r = -0.5709). Similarly, in vivo studies using tumor xenografted mice showed that tumors sensitive to YM155 demonstrated robust uptake of [C-11]YM155, whereas insensitive tumors demonstrated low uptake. In the monkey, the biodistribution of [C-11]YM155 indicated low accumulation in lung, breast, head, and neck and was only significant in organs involved with drug clearance: i.e. liver, kidneys, and bladder.Conclusions: Robust uptake of [C-11]YM155 by a tumor appears to be a positive predictive marker for a good response to YM155. The findings suggest the potential utility of PET/CT imaging with [C-11]YM155 for selection of patients whose tumors are likely to respond to YM155.Advances in knowledge: YM155 efficacy correlated closely with its in vitro intracellular uptake and uptake on [C-11]YM155 PET imaging. [C-11]YM155 PET may predict tumor sensitivity to YM155.Implications for patient care: The concept that tumor response can be accurately predicted prior to chemotherapy should be exploited to improve cancer treatment outcomes through judicious patient selection. The small molecule sepantronium bromide (YM155), a survivin suppressant, has been developed for the treatment of several cancers, including non-Hodgkin lymphoma, lung cancer, and breast cancer. The preferentially high in vitro uptake of YM155 by YM155-sensitive cancer cells and the high in vivo uptake of [C-11]YM155 in YM155-sensitive tumors demonstrated by PET imaging suggest the potential utility of performing [C-11]YM155 PET to allow the identification of patients with YM155-sensitive tumors. (C) 2018 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.nucmedbio.2018.06.005

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  • Design and Synthesis of an Easily Obtainable Maleimide Reagent N-[2-(4-[18F]fluoro-N-methylbenzenesulfonamido)ethyl]maleimide ([18F]FBSEM) to Radiolabel Thiols in Proteins. International journal

    Yuji Fujita, Yoshihiro Murakami, Akihiro Noda, Sosuke Miyoshi

    Bioconjugate chemistry   28 ( 2 )   642 - 648   2017.2

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    An easily obtainable thiol-selective labeling reagent [18F]FBSEM (N-[2-(4-[18F]fluoro-N-methylbenzenesulfonamido)ethyl]maleimide) was developed. The advantage of the design is that the precursor and [18F]FBSEM have the same backbone and backbone construction is not required; in contrast, known thiol-specific labeling reagents do require backbone construction, and this is thought to be the cause of their complicated synthesis. [18F]FBSEM was successfully obtained in higher yield (25%) and in a simpler way (two fluorination and deprotection steps in 65 min) than the widely used [18F]FBEM (N-[2-(4-[18F]fluorobenzamide)ethyl]maleimide). The labeling efficacy of [18F]FBSEM was confirmed by conjugation with glutathione. [18F]FBSEM is a promising labeling agent for proteins.

    DOI: 10.1021/acs.bioconjchem.6b00707

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  • Preclinical Evaluation of an Anti-Nectin-4 ImmunoPET Reagent in Tumor-Bearing Mice and Biodistribution Studies in Cynomolgus Monkeys. International journal

    Dean O Campbell, Akihiro Noda, Alla Verlinsky, Josh Snyder, Yuji Fujita, Yoshihiro Murakami, Hiroshi Fushiki, Sosuke Miyoshi, Sergio Lacayo, Edward Cabral, Peng Yang, David R Stover, Ingrid B J K Joseph

    Molecular imaging and biology   18 ( 5 )   768 - 75   2016.10

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    PURPOSE: Nectin-4 is selectively overexpressed in a variety of cancers and is currently under clinical investigation as a therapeutic target. A monoclonal antibody against nectin-4 (AGS-22M6) was evaluated as an Immuno-positron emission tomography (ImmunoPET) reagent. Its ability to assay nectin-4 expression as well as detect nectin-4 positive tumors in the liver and bone was evaluated using mouse models. PROCEDURES: The biodistribution of [(89)Zr]AGS-22M6 was evaluated in mice bearing tumors with varying levels of nectin-4 expression. An isogenic breast cancer tumor line was used to model metastatic liver and bone disease in mice. The biodistribution of [(18)F]AGS-22M6 in cynomolgus monkeys was evaluated. RESULTS: A positive correlation was demonstrated between tumor nectin-4 expression and [(89)Zr]AGS-22M6 uptake. Tumors in the liver and bone were detected and differentiated based on nectin-4 expression. [(18)F]AGS-22M6 showed limited uptake in cynomolgus monkey tissues. CONCLUSIONS: [(89)Zr]AGS-22M6 is a promising ImmunoPET reagent that can assay nectin-4 expression in both primary and metastatic lesions.

    DOI: 10.1007/s11307-016-0953-x

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  • Functional imaging of pharmacological action of SGLT2 inhibitor ipragliflozin via PET imaging using 11C-MDG. International journal

    Keisuke Mitsuoka, Yuka Hayashizaki, Yoshihiro Murakami, Toshiyuki Takasu, Masanori Yokono, Nobuhiro Umeda, Shoji Takakura, Akihiro Noda, Sosuke Miyoshi

    Pharmacology research & perspectives   4 ( 4 )   e00244   2016.8

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    Sodium-dependent glucose cotransporter 2 (SGLT2) is a pharmacological target of type 2 diabetes mellitus. The aim of this study was to noninvasively visualize the pharmacological action of a selective SGLT2 inhibitor ipragliflozin in the kidney using positron emission tomography (PET) imaging with 11C-methyl-d-glucoside (11C-MDG), an SGLT-specific radio-labeled substrate. PET imaging with 11C-MDG in vehicle-treated rats demonstrated that intravenously injected 11C-MDG substantially accumulated in the renal cortex, reflecting that the compound was reabsorbed by SGLTs. In contrast, ipragliflozin-treated rats showed significantly lower uptake of 11C-MDG in renal cortex in a dose-related manner, suggesting that ipragliflozin inhibited the renal reabsorption of 11C-MDG. This method of visualizing the mode of action of an SGLT2 inhibitor in vivo has demonstrated the drug's mechanism in reducing renal glucose reabsorption in kidney in living animals.

    DOI: 10.1002/prp2.244

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  • Synthesis, SAR study, and biological evaluation of novel quinoline derivatives as phosphodiesterase 10A inhibitors with reduced CYP3A4 inhibition. International journal

    Wataru Hamaguchi, Naoyuki Masuda, Satoshi Miyamoto, Yasuhiro Shiina, Shigetoshi Kikuchi, Takuma Mihara, Hiroyuki Moriguchi, Hiroshi Fushiki, Yoshihiro Murakami, Yasushi Amano, Kazuya Honbou, Kouji Hattori

    Bioorganic & medicinal chemistry   23 ( 2 )   297 - 313   2015.1

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    A novel class of phosphodiesterase 10A inhibitors with potent PDE10A inhibitory activity and reduced CYP3A4 inhibition was designed and synthesized starting from 2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]oxy}methyl)phenyl]quinoline (1). Replacement of pyridine ring of 1 with N-methyl pyridone ring drastically improved CYP3A4 inhibition, and further optimization of these quinoline analogues identified 1-methyl-5-(1-methyl-3-{[4-(quinolin-2-yl)phenoxy]methyl}-1H-pyrazol-4-yl)pyridin-2(1H)-one (42b), which showed potent PDE10A inhibitory activity and a good CYP3A4 inhibition profile. A PET study with (11)C-labeled 42b indicated that 42b exhibited good brain penetration and specifically accumulated in the rodent striatum. Further, oral administration of 42b dose-dependently attenuated phencyclidine-induced hyperlocomotion in mice with an ED50 value of 2.0mg/kg and improved visual-recognition memory impairment at 0.1 and 0.3mg/kg in mice novel object recognition test.

    DOI: 10.1016/j.bmc.2014.11.039

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  • PET imaging for tyrosine kinase inhibitor (TKI) biodistribution in mice. International journal

    Hiroshi Fushiki, Yoshihiro Murakami, Sosuke Miyoshi, Shintaro Nishimura

    Methods in molecular biology (Clifton, N.J.)   1219   199 - 206   2015

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    Receptor tyrosine kinases play a critical role in cell growth, survival, and proliferation, and are considered potential molecular targets for the treatment of cancer. Although several tyrosine kinase inhibitors (TKIs), such as erlotinib and gefitinib, have demonstrated clinical efficacy via the inhibition of the epidermal growth factor receptor (EGFR), most TKIs are only effective in a small proportion of patients. Positron emission tomography (PET) imaging is a methodology of molecular imaging based on nuclear imaging. PET imaging in combination with radiolabeled TKIs improves accuracy of quantitative imaging strategies and the probability of successful drug development, and may facilitate the stratification of patients. Here, we describe a protocol for PET imaging using radiolabeled TKI in preclinical trials.

    DOI: 10.1007/978-1-4939-1661-0_15

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  • Pre-clinical validation of orthotopically-implanted pulmonary tumor by imaging with 18F-fluorothymidine-positron emission tomography/computed tomography. International journal

    Hiroshi Fushiki, Sosuke Miyoshi, Akihiro Noda, Yoshihiro Murakami, Hiroshi Sasaki, Makoto Jitsuoka, Keisuke Mitsuoka, Ichiro Matsunari, Shintaro Nishimura

    Anticancer research   33 ( 11 )   4741 - 9   2013.11

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    The development of positron-emission tomography (PET) and X-ray computed tomography (CT) imaging has improved the detection of tumor burden and, in turn, pre-clinical drug development and clinical treatment. In pre-clinical drug development, clinically-relevant murine cancer models, such as orthotopic models of lung cancer, have provided an accurate representation of tumor burden in humans. However, evidence demonstrating the capability of imaging-guided evaluation of these clinically-relevant models is limited. Here, we combined (18)F-fluorothymidine (FLT)-PET/CT imaging and a murine model of human non-small cell lung cancer (NSCLC) to improve the accuracy of anticancer drug evaluation in pre-clinical studies. We found that FLT-PET/CT imaging enabled the progression of pulmonary tumors to be longitudinally monitored rather than FDG-PET/CT. Furthermore, in an efficacy study of a standard treatment of docetaxel in a murine lung cancer model, FLT-PET imaging detected the anticancer response earlier than volumetric analysis by CT imaging. We, thus, observed a relationship between the alteration of FLT signals and Ki-67 index in the pulmonary tumor during the period of chemotherapy. These results indicate that the combination of FLT-PET/CT imaging and an orthotopic NSCLC model is an effective strategy for evaluating clinical efficacy and potential of an anticancer agent during pre-clinical development.

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  • Radiosynthesis, biodistribution and imaging of [11C]YM155, a novel survivin suppressant, in a human prostate tumor-xenograft mouse model. International journal

    Yoshihiro Murakami, Takahiro Matsuya, Aya Kita, Kentaro Yamanaka, Akihiro Noda, Keisuke Mitsuoka, Takahito Nakahara, Sosuke Miyoshi, Shintaro Nishimura

    Nuclear medicine and biology   40 ( 2 )   221 - 6   2013.2

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    INTRODUCTION: Sepantronium bromide (YM155) is an antitumor drug in development and is a first-in-class chemical entity, which is a survivin suppressant. We developed a radiosynthesis of [(11)C]YM155 to non-invasively evaluate its tissue and tumor distribution in mice bearing human prostate tumor xenografts. METHODS: Methods utilizing [(11)C]acetyl chloride and [(11)C]methyl triflate, both accessible with automated radiosynthesis boxes, were evaluated. The O-methylation of ethanolamine-alkolate with [(11)C]methyl triflate proved to be the key development toward a rapid and efficient process. The whole-body distribution of [(11)C]YM155 in PC-3 xenografted mice was examined using a planar positron imaging system (PPIS). RESULTS: Sufficient quantities of radiopharmaceutical grade [(11)C]YM155 were produced for our PET imaging and distribution studies. The decay corrected (EOB) radiochemical yield was 16-22%, within a synthesis time of 47 min. The radiochemical purity was higher than 99%, and the specific activity was 29-60 GBq/μmol (EOS). High uptake levels of radioactivity (%ID/g, mean±SE) were observed in tumor (0.0613±0.0056), kidneys (0.0513±0.0092), liver (0.0368±0.0043) and cecum (0.0623±0.0070). The highest tumor uptake was observed at an early time point (from 10 min after) following injection. Tumor-to-blood and tumor-to-muscle uptake ratios of [(11)C]YM155, at 40 min after injection, were 26.5 (±2.9) and 25.6 (±3.6), respectively. CONCLUSION: A rapid method for producing a radiopharmaceutical grade [(11)C]YM155 was developed. An in vivo distribution study using PPIS showed high uptake of [(11)C]YM155 in tumor tissue. Our methodology may facilitate the evaluation and prediction of response to YM155, when given as an anti-cancer agent.

    DOI: 10.1016/j.nucmedbio.2012.10.002

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  • Brain penetration of telmisartan, a unique centrally acting angiotensin II type 1 receptor blocker, studied by PET in conscious rhesus macaques. International journal

    Akihiro Noda, Hiroshi Fushiki, Yoshihiro Murakami, Hiroshi Sasaki, Sosuke Miyoshi, Hirotoshi Kakuta, Shintaro Nishimura

    Nuclear medicine and biology   39 ( 8 )   1232 - 5   2012.11

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    INTRODUCTION: Telmisartan is a widely used, long-acting antihypertensive agent. Known to be a selective angiotensin II type 1 (AT(1)) receptor (AT(1)R) blocker (ARB), telmisartan acts as a partial agonist of peroxisome proliferator-activated receptor-gamma (PPAR-γ) and inhibits centrally mediated effects of angiotensin II in rats following peripheral administration, although the brain penetration of telmisartan remains unclear. We investigated the brain concentration and localization of telmisartan using (11)C-labeled telmisartan and positron emission tomography (PET) in conscious rhesus macaques. METHODS: Three male rhesus macaques were bolus intravenously administered [(11)C]telmisartan either alone or as a mixture with unlabeled telmisartan (1mg/kg). Dynamic PET images were acquired for 95min following administration. Blood samples were collected for the analysis of plasma concentration and metabolites, and brain and plasma concentrations were calculated from detected radioactivity using the specific activity of the administered drug preparation, in which whole blood radioactivity was used for the correction of intravascular blood radioactivity in brain. RESULTS: Telmisartan penetrated into the brain little but enough to block AT(1)R and showed a consistently increasing brain/plasma ratio within the PET scanning period, suggesting slow clearance of the compound from the brain compared to the plasma clearance. Brain/plasma ratios at 30, 60, and 90min were 0.06, 0.13, and 0.18, respectively. No marked localization according to the AT(1)R distribution was noted over the entire brain, even on tracer alone dosing. CONCLUSIONS: Telmisartan penetrated into the brain enough to block AT(1)R and showed a slow clearance from the brain in conscious rhesus macaques, supporting the long-acting and central responses of telmisartan as a unique property among ARBs.

    DOI: 10.1016/j.nucmedbio.2012.06.012

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  • Inhibition of oligopeptide transporter suppress growth of human pancreatic cancer cells. International journal

    Keisuke Mitsuoka, Yukio Kato, Sosuke Miyoshi, Yoshihiro Murakami, Mariko Hiraiwa, Yoshiyuki Kubo, Shintaro Nishimura, Akira Tsuji

    European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences   40 ( 3 )   202 - 8   2010.6

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    Oligopeptide transporters are abundantly expressed in various types of cancer cells. We here synthesized two novel dipeptides, l-phenylalanyl sarcosine (Phe-Sar) and 4-(4-methoxyphenyl)-l-phenylalanyl sarcosine (Bip(OMe)-Sar), and examined their effect on the growth of human pancreatic cancer AsPC-1 cells, which are known to highly express oligopeptide transporter PEPT1/SLC15A1. Growth of AsPC-1 cells was inhibited by these two peptides and a typical PEPT1/SLC15A1 substrate Gly-Sar. Growth inhibition by Gly-Sar, Phe-Sar and Bip(OMe)-Sar was concentration-dependent with half-maximal inhibitory concentration of 50, 0.91 and 0.55mM, respectively. These peptides also inhibited PEPT1-mediated [(3)H]Gly-Sar uptake with half-maximal inhibitory concentration of 2.6, 0.81 and 0.27mM, respectively. Thus, the rank order of the tumor cell growth inhibition by these three peptides was the same as that of PEPT1-inhibitory activity. Growth of AsPC-1 cells was also inhibited by 2-aminobicyclo(2,2,1)heptane-2-carboxylic acid (BCH), which is a typical inhibitor of amino acid transporter system L. The growth inhibition by BCH and Gly-Sar was additive, suggesting that these compounds act at distinct loci. Oligopeptide transporters thus appear to be a promising target for inhibition of pancreatic cancer progression. These results also proposed the idea that oligopeptide transporter is required for growth of AsPC-1 cells.

    DOI: 10.1016/j.ejps.2010.03.010

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  • Evaluation of the kappa-opioid receptor-selective tracer [(11)C]GR103545 in awake rhesus macaques. International journal

    Bent W Schoultz, Trine Hjornevik, Frode Willoch, János Marton, Akihiro Noda, Yoshihiro Murakami, Sosuke Miyoshi, Shintaro Nishimura, Erik Arstad, Alexander Drzezga, Ichiro Matsunari, Gjermund Henriksen

    European journal of nuclear medicine and molecular imaging   37 ( 6 )   1174 - 80   2010.6

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    PURPOSE: The recent development in radiosynthesis of the (11)C-carbamate function increases the potential of [(11)C]GR103545, which for the last decade has been regarded as promising for imaging the kappa-opioid receptor (kappa-OR) with PET. In the present study, [(11)C]GR103545 was evaluated in awake rhesus macaques. Separate investigations were performed to clarify the OR subtype selectivity of this compound. METHODS: Regional brain uptake kinetics of [(11)C]GR103545 was studied 0-120 min after injection. The binding affinity and opioid subtype selectivity of [(11)C]GR103545 was determined in cells transfected with cloned human opioid receptors. RESULTS: In vitro binding assays demonstrated a high affinity of GR103545 for kappa-OR (K(i) = 0.02 +/- 0.01 nM) with excellent selectivity over mu-OR (6 x 10(2)-fold) and) delta-OR (2 x 10(4)-fold). PET imaging revealed a volume of distribution (V(T)) pattern consistent with the known distribution of kappa-OR, with striatum = temporal cortex > cingulate cortex > frontal cortex > parietal cortex > thalamus > cerebellum. CONCLUSION: [(11)C]GR103545 is selective for kappa-OR and holds promise for use to selectively depict and quantify this receptor in humans by means of PET.

    DOI: 10.1007/s00259-010-1384-6

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  • Brain adenosine A2A receptor occupancy by a novel A1/A2A receptor antagonist, ASP5854, in rhesus monkeys: relationship to anticataleptic effect. International journal

    Takuma Mihara, Akihiro Noda, Hiroshi Arai, Kayoko Mihara, Akinori Iwashita, Yoshihiro Murakami, Takahiro Matsuya, Sosuke Miyoshi, Shintaro Nishimura, Nobuya Matsuoka

    Journal of nuclear medicine : official publication, Society of Nuclear Medicine   49 ( 7 )   1183 - 8   2008.7

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    UNLABELLED: The purpose of the present study was to measure adenosine A(2A) receptor (A(2A)R) occupancy in the brain by a novel adenosine A(1)/A(2A) antagonist, 5-[5-amino-3-(4fluorophenyl)pyrazin-2-yl]-1-isopropylpyridine-2(1H)-one (ASP5854), and to determine the degree of receptor occupancy necessary to inhibit haloperidol-induced catalepsy in rhesus monkeys. METHODS: A(2A)R occupancy by ASP5854 (0.001-0.1 mg/kg) was examined in the striatum using an A(2A)R-specific radiotracer, (11)C-SCH442416, and PET in conscious rhesus monkeys. A(2A)R occupancy was monitored after a single intravenous administration of ASP5854 in 3 animals, and a dynamic PET scan was performed at 1, 4, and 8 h after an intravenous bolus injection of the tracer for approximately 740 MBq. Catalepsy was induced by haloperidol (0.03 mg/kg, intramuscularly) and examined for incidence and duration. RESULTS: ASP5854 dose-dependently increased A(2A)R occupancy in the striatum and showed long-lasting occupancy even after the reduction of plasma concentration. Haloperidol induced severe catalepsy at 40 min after intramuscular injection. The incidence and duration of cataleptic posture were dose-dependently reduced by ASP5854 at 1 h after oral administration, and the minimum ED(50) value was 0.1 mg/kg. Administration of a dose of 0.1 mg/kg yielded a plasma concentration of 97 +/- 16.3 ng/mL, which corresponded to 85%-90% of A(2A)R occupancy. CONCLUSION: These results showed that ASP5854 antagonized A(2A)R in the striatum, and the dissociation from A(2A)R was relatively slow. In addition, more than 85% A(2A)R occupancy by ASP5854 resulted in an inhibition of haloperidol-induced catalepsy. Thus, such a pharmacodynamic study directly demonstrates both the kinetics of a drug in the brain and the relationship between dose-dependent receptor occupancy and plasma level.

    DOI: 10.2967/jnumed.108.051474

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  • Amyloid imaging in aged and young macaques with [11C]PIB and [18F]FDDNP. International journal

    Akihiro Noda, Yoshihiro Murakami, Shingo Nishiyama, Dai Fukumoto, Sosuke Miyoshi, Hideo Tsukada, Shintaro Nishimura

    Synapse (New York, N.Y.)   62 ( 6 )   472 - 5   2008.6

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    [11C]PIB and [18F]FDDNP were examined on five aged and five young adult male rhesus macaques using positron emission tomography. Both tracers showed increased accumulation in the striatum, thalamus, cingulate and pons in the aged group. Compared to [11C]PIB, [18F]FDDNP showed higher accumulation in the cortical regions of aged animals as well as young animals. Although [18F]FDDNP may have possible usefulness for imaging, including other proteins, [11C]PIB may be better for amyloid imaging owing to lower non-specific binding.

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  • Cancer detection using a PET tracer, 11C-glycylsarcosine, targeted to H+/peptide transporter. International journal

    Keisuke Mitsuoka, Sosuke Miyoshi, Yukio Kato, Yoshihiro Murakami, Rie Utsumi, Yoshiyuki Kubo, Akihiro Noda, Yukio Nakamura, Shintaro Nishimura, Akira Tsuji

    Journal of nuclear medicine : official publication, Society of Nuclear Medicine   49 ( 4 )   615 - 22   2008.4

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    UNLABELLED: H+/peptide transporter, PEPT1, is functionally expressed in some human cancer cell lines and might be a candidate molecular target for detection of cancers in vivo using PET. The aim of the present study was to establish a novel tumor-imaging technology using a PET tracer targeted to H+/peptide transporter(s). We also compared the tracer with 18F-FDG, focusing on the specificity of their accumulation between tumor and inflammatory tissues. METHODS: A dipeptide PET tracer, 11C-glycylsarcosine (11C-Gly-Sar), was injected intravenously into athymic mice transplanted with human pancreatic, prostate, and gastric cancer cells. The distribution patterns of 11C-Gly-Sar and 18F-FDG in the tumor-bearing mice, and in mice with inflammatory tissue, were assessed by imaging with a positron planar imaging system (PPIS). Tissue distributions of tracer radioactivity were also measured. The expression levels of PEPT1 and PEPT2 (PEPTs) proteins in tumor xenografts and inflammatory tissue were examined by immunohistochemical analysis. The messenger RNA expression levels of PEPTs in 58 available cancer cell lines were quantified by means of real-time polymerase chain reaction. RESULTS: All 3 tumor xenografts were well visualized with the PPIS after injection of 11C-Gly-Sar. Expression of PEPTs in those xenografts was confirmed by immunohistochemical analysis. Tumor-to-blood concentration ratios of 11C-Gly-Sar increased in a time-dependent manner and were much higher than unity. Most of the radioactivity found in the tumor tissue was recovered as the intact tracer. These results indicated that 11C-Gly-Sar was taken up by the PEPTs in tumor xenografts. It is noteworthy that 11C-Gly-Sar was minimally present in inflammatory tissues that expressed no PEPT1 or PEPT2 protein, whereas 18F-FDG was highly accumulated, with the values of the selectivity index being >25.1 and 0.72 for 11C-Gly-Sar and 18F-FDG, respectively. The mRNAs of PEPT1 and PEPT2 were expressed in 27.6% and 93.1%, respectively, of the cancer cell lines examined in the present study. CONCLUSION: The present study indicates that 11C-Gly-Sar is a promising tumor-imaging agent and is superior to 18F-FDG for distinguishing between tumors and inflammatory tissue. Because PEPTs were ubiquitously expressed in various types of tumor cells examined, 11C-Gly-Sar could be useful for the detection of many types of cancers.

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  • PET measurement of FK506 concentration in a monkey model of stroke. International journal

    Yoshihiro Murakami, Hiroyuki Takamatsu, Akihiro Noda, Kazuhiko Osoda, Shintaro Nishimura

    Nuclear medicine and biology   34 ( 6 )   703 - 7   2007.8

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    INTRODUCTION: The immunosuppressive agent FK506 (tacrolimus) has neuroprotective properties in an experimental model of cerebral ischemia. To improve the accuracy of clinical studies in acute stroke, a clinical dose setting should be based on the brain concentration, but not on the blood concentration of agents in humans. We have already established a measurement method using PET for FK506 concentration in the normal monkey brain, which could be applicable for human study; however, under ischemic conditions, in this study, we aimed to examine the brain concentration of FK506 in a monkey model of stroke. METHODS: Studies were performed on six male cynomolgus monkeys (Macaca fascicularis) and a middle cerebral artery (MCA) occlusion model was used. Regional cerebral blood flow (rCBF) was measured by an intravenous injection of [(15)O]H(2)O 165 min after MCA occlusion. FK506 (0.1 mg/kg) containing [(11)C]FK506 was intravenously injected into the monkeys 180 min after MCA occlusion, and dynamic PET images were acquired for 30 min after administration. FK506 concentrations in the brain were calculated in moles per liter (M) units using the specific activity of injected FK506. RESULTS: MCA occlusion produced ischemia, confirmed by rCBF measurement before the administration of [(11)C]FK506. Fifteen minutes after FK506 (0.1 mg/kg) administration, the concentrations in the contralateral and ipsilateral cortex were 22.4+/-6.4 and 19.7+/-4.0 ng/g, respectively. CONCLUSION: We successfully measured the brain concentration of FK506 in a monkey model of stroke. The difference between the contralateral and ipsilateral concentrations of FK506 was not significant. This characteristic that FK506 readily penetrates ischemic tissue as well as normal tissue might explain the neuroprotective effect of FK506 in the ischemic brain and is suitable for the treatment of stroke patients.

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  • Synergistic effects of adenosine A2A antagonist and L-DOPA on rotational behaviors in 6-hydroxydopamine-induced hemi-Parkinsonian mouse model.

    Takahiro Matsuya, Kazuhiro Takuma, Kosuke Sato, Makoto Asai, Yoshihiro Murakami, Sosuke Miyoshi, Akihiro Noda, Taku Nagai, Hiroyuki Mizoguchi, Shintaro Nishimura, Kiyofumi Yamada

    Journal of pharmacological sciences   103 ( 3 )   329 - 32   2007.3

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    In this study, we examined the combination effects of L-DOPA and adenosine receptor antagonists on rotational behaviors in a hemi-Parkinsonian mouse model induced by unilateral 6-hydroxydopamine (6-OHDA) injection. The adenosine A(2A) antagonist SCH-58261, but not the A(1)-receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine or A(2B)-receptor antagonist alloxazine, synergistically potentiated the L-DOPA-induced rotational behaviors in the 6-OHDA-lesioned mice. In addtion, the 6-OHDA-induced lesions of the dopaminergic system did not affect the in vivo binding of an adenosine A(2A)-receptor tracer [(11)C]SCH-442416 in the striatatum. These findings suggest that adenosine A(2A) antagonists are extremely useful for pharmacotherapy of L-DOPA in Parkinson's disease patients.

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  • Synthesis and bioimaging of positron-emitting 15O-labeled 2-deoxy-D-glucose of two-minute half-life. International journal

    Hideki Yorimitsu, Yoshihiro Murakami, Hiroyuki Takamatsu, Shintaro Nishimura, Eiichi Nakamura

    Chemistry, an Asian journal   2 ( 1 )   57 - 65   2007.1

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    In positron emission tomography (PET), which exploits the affinity of a radiopharmaceutical for the target organ, a systematic repertoire of oxygen-15-labeled PET tracers is expected to be useful for bioimaging owing to the ubiquity of oxygen atoms in organic compounds. However, because of the 2-min half-life of 15O, the synthesis of complex biologically active 15O-labeled organic molecules has not yet been achieved. A state-of-the-art synthesis now makes available an 15O-labeled complex organic molecule, 6-[15O]-2-deoxy-D-glucose. Ultrarapid radical hydroxylation of 2,6-dideoxy-6-iodo-D-glucose with molecular oxygen labeled with 15O of two-minute half-life provided the target 15O-labeled molecule. The labeling reaction with 15O was complete in 1.3 min, and the entire operation time starting from the generation of 15O-containing dioxygen by a cyclotron to the purification of the labeled sugar was 7 min. The labeled sugar accumulated in the metabolically active organs as well as in the bladder of mice and rats. 15O-labeling offers the possibility of repetitive scanning and the use of multiple PET tracers in the same body within a short time, and hence should significantly expand the scope of PET studies of small animals.

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  • Quantitation of cardiac sympathetic innervation in rabbits using 11C-hydroxyephedrine PET: relation to 123I-MIBG uptake. International journal

    Yusuke Nomura, Ichiro Matsunari, Hiroyuki Takamatsu, Yoshihiro Murakami, Takahiro Matsuya, Junichi Taki, Kenichi Nakajima, Stephan G Nekolla, Wei-Ping Chen, Kouji Kajinami

    European journal of nuclear medicine and molecular imaging   33 ( 8 )   871 - 8   2006.8

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    PURPOSE: Although (11)C-hydroxyephedrine ((11)C-HED) PET is used to map cardiac sympathetic innervation, no studies have shown the feasibility of quantitation of (11)C-HED PET in small- to medium-sized animals. Furthermore, its relation to (123)I-MIBG uptake, the most widely used sympathetic nervous tracer, is unknown. The aims of this study were to establish in vivo sympathetic nerve imaging in rabbits using (11)C-HED PET, and to compare the retention of (11)C-HED with that of (123)I-MIBG. METHODS: Twelve rabbits were assigned to three groups; control (n=4), chemical denervation by 6-hydroxydopamine (6-OHDA) (n=4) and reserpine treated to inhibit vesicular uptake (n=4). After simultaneous injection of (11)C-HED and (123)I-MIBG, all animals underwent dynamic (11)C-HED PET for 40 min with arterial blood sampling. The (11)C-HED retention fraction and normalised (11)C-HED activity measured by tissue sampling were compared with those measured by PET. RESULTS: Both the (11)C-HED retention fraction and the normalised (11)C-HED activity measured by PET correlated closely with those measured by tissue sampling (R=0.96027, p<0.001 and R=0.97282, p<0.001, respectively). Inhibition study by 6-OHDA resulted in a significant reduction in retention (90%) for both (11)C-HED and (123)I-MIBG. Reserpine pretreatment reduced (11)C-HED retention by 50%, but did not reduce (123)I-MIBG retention at 40 min after injection. CONCLUSION: Non-invasive quantitation of cardiac sympathetic innervation using (11)C-HED PET is feasible and gives reliable estimates of cardiac sympathetic innervation in rabbits. Additionally, although both (11)C-HED and (123)I-MIBG are specific for sympathetic neurons, (11)C-HED may be more specific for intravesicular uptake than (123)I-MIBG in some situations, such as that seen in reserpine pretreatment.

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  • Synthesis and evaluation of [11C]FR194921 as a nonxanthine-type PET tracer for adenosine A1 receptors in the brain. International journal

    Takahiro Matsuya, Hiroyuki Takamatsu, Yoshihiro Murakami, Akihiro Noda, Rikiya Ichise, Yuji Awaga, Shintaro Nishimura

    Nuclear medicine and biology   32 ( 8 )   837 - 44   2005.11

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    This report describes the synthesis of [11C]2-(1-methyl-4-piperidinyl)-6-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-3(2H)-pyridazinone ([11C]FR194921), a highly selective, nonxanthine-type adenosine A(1) receptor antagonist, used in brain imaging in rats and conscious monkeys as a potential novel PET tracer. [11C]FR194921 was successfully synthesized in 19 min after [11C]CH3I formation. The radiochemical yield was 38+/-3%; and radioactivity was 4.1+/-0.4 GBq, calculated from end of synthesis; radiochemical purity was higher than 99%; and the specific radioactivity was 25.0+/-8.1 GBq micromol(-1) (n=5). In a rat experiment, the distribution of [11C]FR194921 was higher in the hippocampus, striatum and cerebellum regions. This accumulation was significantly decreased by approximately 50% by pretreatment with 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), an adenosine A1 receptor antagonist, which indicated specific binding of the radioligand to adenosine A1 receptors. In conscious monkey PET experiments, [11C]FR194921 accumulated in several regions of the brain, especially in the occipital cortex, thalamus and striatum. These results suggest that [11C]FR194921 can be used as an agent for imaging adenosine A1 receptors in vivo by positron emission tomography (PET).

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  • Ultra-rapid synthesis of 15O-labeled 2-deoxy-D-glucose for positron emission tomography (PET). International journal

    Hideki Yorimitsu, Yoshihiro Murakami, Hiroyuki Takamatsu, Shintaro Nishimura, Eiichi Nakamura

    Angewandte Chemie (International ed. in English)   44 ( 18 )   2708 - 2711   2005.4

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    DOI: 10.1002/anie.200500044

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  • On-chip micro-flow polystyrene bead-based immunoassay for quantitative detection of tacrolimus (FK506). International journal

    Yoshihiro Murakami, Tatsuro Endo, Shouhei Yamamura, Naoki Nagatani, Yuzuru Takamura, Eiichi Tamiya

    Analytical biochemistry   334 ( 1 )   111 - 6   2004.11

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    Tacrolimus (FK506) is a widely used immunosuppressant for preventing allograft rejection and the treatment of atopic dermatitis. FK506 necessitates therapeutic drug monitoring because of inter- and intrapatient variability and the lack of correlation between the administered dose and the blood concentration. Previous immunoassay-based methods required a relatively long assay time and troublesome liquid-handling procedures. In the present study, we aimed to establish a rapid monitoring method for FK506 determination by using a poly(dimethylsiloxane) (PDMS)-based microfluidic device. Polystyrene beads were coated with mouse anti-FK506 antibody and placed in the flow channel. As a competitive assay, sample solution was allowed to react in the flow channel. After the addition of the fluorogenic substrate, the fluorescent signal was observed under a microscope. As a result, the developed assay allowed a short detection time of approximately 15 min per each sample and a high sensitivity even by using only a single bead. The feasibility of performing a competitive assay using a PDMS-based antibody chip gives promising results over the existing immunoassay-based methods.

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  • Pharmacokinetic animal PET study of FK506 as a potent neuroprotective agent. International journal

    Yoshihiro Murakami, Hiroyuki Takamatsu, Akihiro Noda, Kazuhiko Osoda, Rikiya Ichise, Mitsuyoshi Tatsumi, Kenji Tabata, Taiji Sawamoto, Shintaro Nishimura

    Journal of nuclear medicine : official publication, Society of Nuclear Medicine   45 ( 11 )   1946 - 9   2004.11

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    UNLABELLED: The immunosuppressive agent FK506 (tacrolimus) has neuroprotective properties not only in rodents but also in nonhuman primates. To improve the accuracy of clinical studies of acute stroke, clinical dose setting based on brain concentrations of agents in humans is very helpful. We have already established a rapid-synthesis method for (11)C-labeled FK506; therefore, in the present study, we aimed to establish a method to measure brain concentrations of FK506 using (11)C-FK506 PET in monkeys. METHODS: Studies were performed on 3 male cynomolgus monkeys (Macaca fascicularis). FK506 (0.1 mg/kg) containing (11)C-FK506 was intravenously injected into the monkeys, and dynamic PET images were acquired for 30 min afterward. Arterial blood samples were collected 5 and 15 min after injection, and their radioactivities were measured by a gamma-counter. FK506 concentrations in brain and blood were calculated in units of moles per liter using the specific activity of the injected FK506. The PET study data were validated using an enzyme-linked immunosorbent assay. RESULTS: Seven minutes after administration, the radioactivity in the brain became constant and was maintained up to 30 min. We succeeded in measuring the FK506 concentration in the brain using (11)C-FK506 PET. Fifteen minutes after FK506 (0.1 mg/kg) administration, the concentrations in the cortex and striatum were 20.0 +/- 1.7 ng/g and 14.1 +/- 1.7 ng/g, respectively. FK506 concentrations in the blood correlated significantly with those measured by enzyme-linked immunosorbent assay. CONCLUSION: We successfully measured FK506 concentrations in anesthetized monkey brain and blood using (11)C-FK506 PET. These results indicate a potential method to measure FK506 concentrations in human brain. Additionally, a potential use for the PET technique in drug development has been demonstrated.

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  • 103(P-40) Ultra-rapid Synthesis and Bio-imaging of ^<15>O-Labeled 2-Deoxy-D-glucose

    Yorimitsu Hideki, Murakami Yoshihiro, Takamatsu Hiroyuki, Nishimura Shintaro, Nakamura Eiichi

    Symposium on the Chemistry of Natural Products, symposium papers   ( 46 )   593 - 598   2004.10

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    In positron emission tomography (PET), a systematic repertoire of oxygen-15-labeled PET tracers would be useful owing to the ubiquity of oxygen atoms in organic compounds. Because of the 2-min half-life of ^<15>O, however, no organic compounds more complex than 1-|^<15>O|butanol have been available. The synthesis of an ^<15>O-labeled complex organic molecule being ever possible and practically useful, it must be exceedingly rapid and clean. In the light of the capability of PET to image in vivo glucose metabolism, we have chosen 6-|^<15>O|-2-deoxy-D-glucose (|^<15>O|DG) as our first target to establish the feasibility of the required ultra-rapid organic synthesis, which we report herein. We previously developed a radical oxygenation reaction starting with an alkyl halide, air, Bu_3SnH and a small amount of azobis(isobutyronitrile), and used it for ^<17>O- and ^<18>O-labeling of complex organic molecules. For the ^<15>O-labeling, a number of fundamental problems, however, needed to be resolved: (1) Drastic reduction of the reaction time from over 10 hours in air to a few minutes, fighting against the low-concentration ^<15>O^<16>Ogas supplied, (2) erratic induction time inherent to radical chain reactions, (3) the use of a OH-free sugar substrate to avoid time loss of deprotection, (4) enhancement of the reaction selectivity and (5) a variety of synthetic and operational issues related to radioactivity and automation. To make efficient utilization of the ^<15>O^<16>O gas, we used a CF_3C_6H_5/perfluorodecalin/2-butanol mixture as a solvent. The reactant solution was placed in a reaction vessel equipped with a sintered glass bottom, through which the oxygen gas was introduced as fine bubbles. Purification of the desired labeled sugar employed a solid phase extraction technique. Ultra-rapid radical hydroxylation of 6-iodo-2,6-dideoxy-D-glucose with |^<15>O|O_2 have now made available the ^<15>O-labeled compound, |^<15>O|DG. A saline solution of |^<15>O|DG was prepared and administered to a rat. The distribution of |^<15>O|DG was measured with the aid of a planar positron imaging system. This image is essentially the same as that obtained with 2-deoxy-2-|^<18>F|fluoro-D-glucose (|^<18>|FDG), which reflects the accumulations in the heart, kidneys, and bladder, hence imaging the glucose metabolism in the test animal. We could also perform sequential |^<15>O|DG-|^<15>O|H_2O-|^<18>F|FDG measurement at intervals of five minutes to obtain similar images. The ^<15>O-labeling thus offers repetitive scanning and use of multiple PET tracers in the same body within a short time, and hence will significantly expand the scope of the PET studies.

    DOI: 10.24496/tennenyuki.46.0_593

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  • 18F-labelled annexin V: a PET tracer for apoptosis imaging. International journal

    Yoshihiro Murakami, Hiroyuki Takamatsu, Junichi Taki, Mitsuyoshi Tatsumi, Akihiro Noda, Rikiya Ichise, Jonathan F Tait, Shintaro Nishimura

    European journal of nuclear medicine and molecular imaging   31 ( 4 )   469 - 74   2004.4

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    Annexin V can be used to detect apoptotic cells in vitro and in vivo, based on its ability to identify extracellular phosphatidylserine, which arises during apoptosis. In the present study, we examined the synthesis of fluorine-18 labelled annexin V as a positron emission tomography tracer for apoptosis imaging. The distribution of [18F]annexin V and technetium-99m labelled annexin V, a well-characterised SPET tracer for apoptosis imaging, was compared. [18F]annexin V was synthesised using N-succinimidyl 4-[18F]fluorobenzoate as an 18F labelling reagent. Synthesised and purified [18F]annexin V was confirmed by SDS-PAGE. In an ex vivo imaging experiment, [18F]annexin V was intravenously injected into rats 24 h after the induction of myocardial ischaemia, and accumulation in the left ventricle was examined. [18F]annexin V accumulated in the infarct area of the left ventricle, where apoptotic cells were observed. In separate experiments, [18F]annexin V or [(99m)Tc]annexin V was intravenously injected into ischaemic or normal animals, and the distribution of the tracers was compared. In ischaemic animals, accumulation of [18F]annexin V and [(99m)Tc]annexin V in the infarct area was about threefold higher than in the non-infarct area. Furthermore, the ratio of accumulation in the normal heart to the blood radioactivity was not significantly different between the tracers. In normal animals, however, the uptake of [18F]annexin V in the liver, spleen and kidney was much lower than that of [(99m)Tc]annexin V. The low uptake of [18F]annexin V in these organs might represent an advantage over [(99m)Tc]annexin V.

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  • A PET study after treatment with an anxiety-provoking agent, m-chlorophenyl-piperazine, in conscious rhesus monkeys. International journal

    Hiroyuki Takamatsu, Akihiro Noda, Yoshihiro Murakami, Mitsuyoshi Tatsumi, Rikiya Ichise, Shintaro Nishimura

    Journal of nuclear medicine : official publication, Society of Nuclear Medicine   44 ( 9 )   1516 - 21   2003.9

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    UNLABELLED: Several PET studies have been performed on conscious nonhuman primates to examine brain function. However, it is unclear how anxiety or stress during PET measurements influences brain function. In the present study, we examined the effects of a well-known anxiety-provoking agent, m-chlorophenyl-piperazine (mCPP), on regional cerebral blood flow (rCBF) and the regional cerebral metabolic rate of glucose (rCMRglc) using PET on conscious rhesus monkeys. METHODS: Male rhesus monkeys with experience undergoing PET measurements were used. Twenty and 40 min after mCPP injection (0.2, 1.0, or 5.0 mg/kg intramuscularly; n = 5), rCBF and rCMRglc were measured using an intravenous injection of (15)O-H(2)O and (18)F-FDG, respectively. Physiologic parameters, plasma cortisol, and prolactin levels were monitored during PET measurements. RESULTS: Treatment with mCPP significantly increased rCBF in both the cingulate cortex and striatum in a dose-dependent manner, and bell-shaped reductions in rCMRglc were observed for all regions examined. mCPP also significantly increased plasma cortisol and prolactin levels. Physiologic parameters were not affected by mCPP treatment. CONCLUSION: The present study demonstrates that treatment with the anxiety-provoking agent mCPP significantly affects rCBF and rCMRglc in conscious monkeys. Therefore, since the increases in hormone levels demonstrate that mCPP treatment produced anxiety or stress, these results suggest that anxiety or stress influences conscious brain function. Furthermore, the present study suggests that prevention of anxiety or stress is important when measuring conscious brain function in monkeys.

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  • A PET study following treatment with a pharmacological stressor, FG7142, in conscious rhesus monkeys. International journal

    Hiroyuki Takamatsu, Akihiro Noda, Akeo Kurumaji, Yoshihiro Murakami, Mitsuyoshi Tatsumi, Rikiya Ichise, Shintaro Nishimura

    Brain research   980 ( 2 )   275 - 80   2003.8

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    FG7142 is a benzodiazepine partial inverse agonist, which is known as a pharmacological stressor. Several reports demonstrated that FG7142 produced anxiety in humans, non-human primates, and rodents, and impaired working memory in non-human primates and rodents. In this study, we examined the effect of FG7142 on cerebral blood flow and glucose metabolism using positron emission tomography (PET) in conscious rhesus monkeys. Male rhesus monkeys were intramuscularly treated with FG7142 (0.2 or 1.0 mg/kg, n=5, respectively), and regional cerebral blood flow (rCBF) and regional cerebral metabolic rate of glucose (rCMRglc) were measured by PET 20 min and 40 min after treatment, respectively. During PET measurement, physiological parameters and plasma cortisol levels were monitored. FG7142 significantly decreased rCBF in the thalamus and rCMRglc in all brain regions examined in a dose-dependent manner without changes in physiological parameters. FG7142 also significantly increased plasma cortisol levels. The present study may provide an important insight into the understanding of the pathophysiology of anxiety and stress-related disorders in humans, and strongly suggesting that prevention of anxiety or stress is important when measuring conscious brain function.

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  • Rapid synthesis of 11C-labeled FK506 for positron emission tomography Reviewed

    Yoshihiro Murakami, Akio Kuroda, Kazuhiko Osoda, Shintaro Nishimura

    Tetrahedron Letters   44 ( 4 )   641 - 644   2003.1

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    The present study describes a rapid synthesis method for labeled [11C]FK506 for positron emission tomography (PET). A one-pot reaction from [11C]CH3I, involving a Wittig reaction as the key carbon-carbon bond formation was developed. The chemical process was accomplished using a designed, fully automated synthetic apparatus, and an injectable solution of [11C]FK506 was obtained in only 34 min from [11C]CH3I. The decay-corrected radiochemical yield based on [11C]CH3I was 11.9%, and the specific activity was 39.8 GBq/μmol. © 2003 Elsevier Science Ltd. All rights reserved.

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  • Measurement of brain concentration of FK960 for development of a novel antidementia drug: a PET study in conscious rhesus monkeys. International journal

    Akihiro Noda, Hiroyuki Takamatsu, Yoshihiro Murakami, Kazuyoshi Yajima, Mitsuyoshi Tatsumi, Rikiya Ichise, Shintaro Nishimura

    Journal of nuclear medicine : official publication, Society of Nuclear Medicine   44 ( 1 )   105 - 8   2003.1

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    UNLABELLED: This study used PET to measure the time course of the brain concentration of (18)F-labeled N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate (FK960), a novel antidementia drug, after oral administration to conscious rhesus monkeys. METHODS: Three young-adult male rhesus monkeys were tested. FK960 (0.1 mg/kg) containing about 370 MBq of (18)F-FK960 was administered orally to each monkey. Dynamic PET images were acquired for 4 h from 5 min after the administration. Arterial blood samples were withdrawn during PET scanning and were analyzed by an automatic well gamma-counter and thin-layer chromatography to determine the time course of authentic (18)F-FK960 activity concentration in plasma. FK960 concentrations in brain and plasma were calculated in units of mol/L using the specific activity of FK960 preparations. RESULTS: (18)F-FK960 penetrated the blood-brain barrier and underwent perfusion-dependent distribution in the entire brain. Maximal concentrations in the brain and plasma were 1.11 +/- 0.30 x 10(-7) mol/L (at 3.0 +/- 0.6 h after administration) and 4.04 +/- 1.29 x 10(-7) mol/L (at 2.0 +/- 1.1 h after administration), respectively. CONCLUSION: We succeeded in measuring the FK960 concentration in the brains of conscious monkeys and in plasma after oral administration at a dose of 0.1 mg/kg. The results suggested that this method can measure the FK960 concentration in the human brain, and a potential use of the PET technique in drug development was demonstrated.

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  • Synthesis of 18F labelled FK960, a candidate anti-dementia drug, and PET studies in conscious monkeys Reviewed

    Yoshihiro Murakami, Shintaro Nishimura, Akihiro Noda, Norihiro Harada, Hideo Tsukada

    Journal of Labelled Compounds and Radiopharmaceuticals   45 ( 14 )   1219 - 1228   2002.12

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    The present study demonstrated the synthesis and in vivo study of 18F-labeled N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide (FK960) which is a novel anti-dementia drug candidate. [18F]FK960 was prepared by a one-pot, three reaction sequence, using nucleophilic fluorination, with an automated synthetic apparatus using either ethyl-4-trimethylammonium triflate (1a) or ethyl-4-nitrobenzoate (lb) as the precursor for labeling. Though la gave a higher yield, the specific activity was 50-100 fold higher with 1b. The radiochemical yield of [18F]FK960 was 7-15% (EOB) and the specific activity ranged from 2.0-60.2GBq/μmol depending on the amount of F-18 used. The synthesis time was 2.2-2.9 h. The obtained [18F]FK960 was injected into 3 conscious monkeys (100-120MBq/kg body weight), and distribution images and pharmacokinetic data for [18F]FK960 showed similar uptake in different brain regions and 3-fold higher levels of [18F]FK960 in blood relative to brain. Copyright © 2002 John Wiley &amp
    Sons, Ltd.

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Presentations

  • Synthesis and Characterization of 18F-Labeled 4-Thia-oleic Acid Derivatives for Fatty Acid Beta-Oxidation Imaging.

    Murakami Y, Fujita Y, Fushiki H

    33rd Annual Congress of the European Association of Nuclear Medicine 2020  2020.10 

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  • Preliminary evaluation of a novel PET tracer for fatty acid oxidation, 18F-AS3504073-00.

    Ohshima Y, Yagi Y, Chen X, Muhlig S, Fushiki H, Murakami Y, Higuchi T

    33rd Annual Congress of the European Association of Nuclear Medicine 2020  2020.10 

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  • [18F]AS3504073-00, Reflects Mitochondrial Fatty-Acid Oxidation in Physiological Alterations and Cardiac Disfunctions.

    Fushiki H, Murakami Y

    33rd Annual Congress of the European Association of Nuclear Medicine 2020  2020.10 

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  • Production of [18F]AS3504073-00 for Investigational PET Imaging of Fatty Acid Beta-Oxidation in Human Subjects.

    Murakami Y, Fushiki H

    33rd Annual Congress of the European Association of Nuclear Medicine 2020  2020.10 

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  • Synthesis and Preliminary Evaluation of Metabolically Stable 18F-Labeled PET Tracer for Fatty Acid Beta-Oxidation Imaging.

    Murakami Y, Fujita Y, Fushiki H

    2020.7 

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  • In vitro characterization of a novel PET tracer for fatty acid oxidation, 18F-AS3504073-00.

    Ohshima Y, Yagi Y, Chen X, Muhlig S, Fushiki H, Murakami Y, Higuchi T

    Society of Nuclear Medicine Annual Meeting.  2020.7 

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  • Preclinical Safety Evaluation and Non-Human Primates Dosimetry of [18F]AS3504073-00, a Novel Positron Emission Tomography (PET) Ligand for Fatty-Acid Oxidation (FAO).

    Fushiki H, Noda A, Murakami Y

    Society of Nuclear Medicine Annual Meeting.  2020.7 

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  • Utility of [18F]AS3504073-00, Novel PET Ligand for Fatty-Acid Oxidation, for Cardiac Dysfunction in Monkey and Rodent Model.

    Fushiki H, Murakami Y

    Society of Nuclear Medicine Annual Meeting.  2020.7 

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  • Preclinical demonstration of PET imaging using [18F]AS3504073-00 for Mitochondrial Fatty-Acid Oxidation in Rodent and Monkey Heart Failure Models- New Insight into Metabolic Remodeling in Cardiomyocyte.

    Fushiki H, Murakami Y

    American Society of Nuclear Cardiology  2020 

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  • Discovery of a novel radioligand [11C]AS2471907 for PET imaging of the brain 11b-HSD1.

    Iwashita A, Fushiki H, Fujita Y, Murakami Y, Noda A

    Society of Nuclear Medicine Annual Meeting.  2016.6 

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  • Profiling and occupancy study with PET imaging using a novel radioligand [11C]AS2471907 for brain 11b-HSD1

    Iwashita A, Fushiki H, Fujita Y, Murakami Y, Noda A

    Society of Nuclear Medicine Annual Meeting.  2016.6 

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  • Radiosynthesis of [C-11]YM155 in a cGMP environment for pre-clinical PET-imaging.

    Grierson J, Murakami Y, Williams K, Padgett H, Hackett R, Chilton H, Minoshima S, Miyoshi S

    Society of Nuclear Medicine Annual Meeting.  2015.6 

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  • Rapid synthesis and PET imaging of [11C]YM155, a step in advance for prediction of tumor response.

    Murakami Y, Matsuya T, Kita A, Yamanaka K, Noda A, Mitsuoka K, Nakahara T, Miyoshi S, Nishimura S

    Tateshina Conference on Organic Chemistry  2012.11 

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Industrial property rights

  • 陽電子放出核種で標識された脂肪酸誘導体

    村上 佳裕, 伏木 洋司, 藤田 優史

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    Applicant:アステラス製薬株式会社

    Application no:JP2019028380  Date applied:2019.7

    Publication no:WO2020-017620  Date published:2020.1

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  • 腫瘍の画像診断用標識誘導体

    村上 佳裕, 三好 荘介, 野田 昭宏, 光岡 圭介, 実岡 誠, 松矢 高広, 喜多 彩, 山中 堅太郎, 中原 崇人

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    Applicant:アステラス製薬株式会社

    Application no:特願2011-115628  Date applied:2011.5

    Announcement no:特開2014-156400  Date announced:2014.8

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  • 物質の定量方法及び物質の定量デバイス

    民谷 栄一, 遠藤 達郎, 村上 佳裕

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    Applicant:独立行政法人科学技術振興機構

    Application no:特願2006-531695  Date applied:2005.8

    Patent/Registration no:特許第4253695号  Date registered:2009.2 

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  • 新規15O標識モノサッカリドおよびその製造方法

    西村 伸太郎, 村上 佳裕, 中村 栄一, 依光 英樹

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    Applicant:アステラス製薬株式会社

    Application no:特願2006-536905  Date applied:2005.3

    Patent/Registration no:特許第4869937号  Date registered:2011.11 

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  • 血栓造影剤

    村上 佳裕, 青木 俊明, 高松 宏幸, 西村 伸太郎, 襲田 一彦

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    Applicant:アステラス製薬株式会社

    Application no:特願2006-510171  Date applied:2005.1

    Patent/Registration no:特許第4910695号  Date registered:2012.1 

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  • インジェクション装置及びインジェクション方法

    矢嶋 一賀, 村上 佳裕, 繁田 知秀, 上川 忠文

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    Applicant:アステラス製薬株式会社

    Application no:特願2003-148627  Date applied:2003.5

    Announcement no:特開2004-354058  Date announced:2004.12

    Patent/Registration no:特許第3921183号  Date registered:2007.2 

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  • カルバペネム誘導体の製造法およびその中間体

    村田 正好, 笠原 千義, 津々美 秀雄, 村上 佳裕

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    Applicant:藤沢薬品工業株式会社

    Application no:特願平6-022575  Date applied:1994.2

    Announcement no:特開平7-002857  Date announced:1995.1

    J-GLOBAL

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  • 3-置換オキシ-1-アザビシクロ[3.2.0]ヘプト-2-エン-2-カルボン酸化合物

    村田 正好, 津々美 秀雄, 笠原 千義, 村上 佳裕

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    Applicant:藤沢薬品工業株式会社

    Application no:特願平4-267707  Date applied:1992.10

    Announcement no:特開平6-116268  Date announced:1994.4

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Awards

  • Alavi-Mandel Award

    2005.6   Society of Nuclear Medicine and Molecular Imaging   Pharmacokinetic animal PET study for FK506 as a potent neuroprotective agent

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