| Project/Area Number |
12557007
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
General pharmacology
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| Research Institution | Tohoku University |
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Principal Investigator |
YANAI Kazuhiko TOHOKU UNIVERSITY SCHOOL OF MEDICINE, PROFESSOR, 大学院・医学系研究科, 教授 (50192787)
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| Co-Investigator(Kenkyū-buntansha) |
IWATA Ren TOHOKU UNIVERSITY, CYCLOTRON AND RADIOISOTOPE CENTER, PROFESSOR, サイクロトロンRIセンター, 教授 (60143038)
ITOH Masatoshi TOHOKU UNIVERSITY, CYCLOTRON AND RADIOISOTOPE CENTER, PROFESSOR, サイクロトロンRIセンター, 教授 (00125501)
SAKURADA Shinobu TOHOKU PHARMACEUTICAL UNIVERSITY, PROFESSOR, 薬学部, 教授 (30075816)
FUJII Toshihiko DAINIPPON PHARMACEUTICAL CO.,Ltd, RESEARCH DIRECTOR, 開発研究所長
HATANO Kentaro NATIONAL INSTITUTE FOR LONGEVITY SCIENCES, CHIEF RESEARCHER, 室長 (50228475)
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| Project Period (FY) |
2000 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥12,800,000 (Direct Cost: ¥12,800,000)
Fiscal Year 2002: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 2001: ¥4,400,000 (Direct Cost: ¥4,400,000)
Fiscal Year 2000: ¥6,500,000 (Direct Cost: ¥6,500,000)
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| Keywords | Knockout mice / PET / drug development / histamine / acetylcholine esterase / ^<11>C-donepezil / activation study / pain perception / 痛みの受客 / けいれんキンドリング / アレキシサイミア / PET / モルヒネ / carbn-11 / ヒスタミンH_1,H_2受容体 / ダブルノックアウトマウス / ストレス / セロトニン / モルセネ / ^<11>C |
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| Research Abstract |
Knockout mice and positron emission tomography (PET) are unique methods to evaluate the efficacy of administered drugs in vivo. Using recently-developed new technologies, we developed several new methods to evaluate pharmacological effects in vivo in mice and humans. For studies of knockout mice, we discovered several new functions of the histaminergic neurons. H1 blockers can be used as mild analgesics because histamine-related knockout mice showed reduced nociception to various chemical stimuli and enhanced morphine-induced antinociception. We also demonstrated that pentylenetetrazol-kindling were significantly augmented in histamine H1 receptor knockout mice, histidine decarboxylase deficient mice and mast cell deficient mice, suggesting that chronic treatment of brain-penetrating H1 blockers could develop chronic epilepsy in patients. For the development of PET techniques, specific ^<11>C- or ^<18>F-labelled radiotracers for selective labeling of several receptors were newly synthe
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sized by new synthetic methods. Newly-developed tracers are as follows: ^<11>C-donepezil(acetylcholine esterase inhibitor), ^<18>F-TAK147(acetylcholine esterase inhibitor), ^<18>F-fluorocholine (choline analog), and ^<18>F-fuoroproxytan(histamine H3 antagonist). As a new labeling method, 4-[18F]fluorobenzyl halides and [^<11>C]methyl triflate were synthesized and used to label radioplmramaceuticals. We also developed several new methods of imaging in the human brain using 3-demensional PET system. Our developed PET methods for human neuropharmacology are as follows: Non-invasive measurement of receptor binding parameters; cerebral activation study with H_2^<15>O and 3D-PET; ^<11>C-ligand activation study to measure neurotransmiter release. To understand the brain mechanism of personal characters, we clarified the significant difference in brain processing of emotion by facial expressions in alexithymia using 3D-PET and H_2^<15>O. For neuroreceptor studies, we examined the alternation of histaminergic neurotransmission in depressive and schizophrenic patients. H1 receptor bindings were significantly decreased in brains of both psychiatric diseases. Less
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