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The new perspectives of knockout mice and positron emission temography in the development and evaluation of drugs

Research Project

Project/Area Number 12557007
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field General pharmacology
Research InstitutionTohoku University

Principal Investigator

YANAI Kazuhiko  TOHOKU UNIVERSITY SCHOOL OF MEDICINE, PROFESSOR, 大学院・医学系研究科, 教授 (50192787)

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)
Project Period (FY) 2000 – 2002
Project Status Completed (Fiscal Year 2002)
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)
KeywordsKnockout 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
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 … More 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

Report

(4 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • 2000 Annual Research Report
  • Research Products

    (33 results)

All Other

All Publications (33 results)

  • [Publications] J.I.Mobarakeh, et al.: "Improgan antinociception does not require neuronal histamine or histamine receptors"Brain Res. 974(1-2). 146-152 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] M.Kano, et al.: "Specific brain processing of emotion by facial expressions in alexithymia : a H_2 ^<15>O-PET study"Brain. (印刷中). (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Z.Chen, et al.: "Chemical kindling induced by pentylenetetrazol in histamine H_1 receptor gene knockout mice, HDC knockout mice, and mast cell deficient W/W^v mice"Brain Res. 968. 162-166 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] H.Toyota, et al.: "Behavioral characterization of mice lacking histamine H_3 receptors"Mol. Pharmacol.. 62. 389-397 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] M.Tagawa, et al.: "Neuroimaging of histamine H_1 receptor occupancy in human brain by positron emission tomography"Br. J. Clin. Pharmacol.. 52(5). 501-509 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] M.Higuchi, et al.: "Histamine H_1 receptors in patients with Alzheimer's disease assessed by positron emission tomography"Neuroscience. 99. 721-729 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Takahiko Watanabe, Henk Timmermenn, Kazuhiko Yanai: "Histamine Research in the New Millennium"Elsevier Science B. V.. 521 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] J.I.Mobarakeh. J.W.Nalwalk. T.Watanabe. S.Sakurada, M.Hoffman, R.Leurs, H.Timmerman, I.Silos-Santiago, K.Yanai and L.B.Hough: "Improgan antimociception does not require neuronal histamine or histamine receptors"Brain Res.. 974(1-2). 146-152 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] M.Kano, S.Fukudo, J.Gyoba, K.Miyuki, M.Tagawa, H.Mochizuki, M.Itoh, M.Hongo, K.Yanai: "Specific brain processing of emotion by facial expressions in alexithymia:a H_2^<15>0-PET study"Brain. in press. (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Z.Chen, Z.Li, E.Sakurai, J.I.Mobarakeh, H.Ohtsu, T.Watanabe, T.Watanabe, K.Iinuma and K Yanai: "Chemical kindling induced by pentylenetetrazol in histamine H_1 receptor gene knockout mice(H_1KO), histidine decarboxylase-deficient mice(HDC^<-/->) and mast cell-deficient W/W^v mice"Brain Res.. 968. 162-166 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] H.Toyota, C.Dugovic, M.Koehl, A.D.Laposky, C.Weber, K.Ngo, Y.Wu, D.H.Lee, K.Yanai, E.Sakurai, T.Watanabe, C.Liu, J.Chen, A.J.Barbier, F.W.Turek, W.-P.Fung-Leung, and T.W.Lovenberg: "Behavioral characterzation of mice lacking histamine H3 receptors"Mol. Pharmacol. 62. 389-397 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] M.Tagawa, M.Kano, N.Okamura, M.Higuchi, M.Matsuda, Y.Mizuki, H.Arai, R.Iwata, T.Fujii, S.Komemushi, T.Ido, M.ltoh, H.Sasaki, T.Watanabe, and K.Yanai: "Neuroimaging of histamine H1-receptor occupancy in human brain by positron emission tomography (PET): A comparative study of ebastine, a second-generation antihistamine, and d-chlorpheniramine, a classical antihistamine"Br.J.Clin.Pharmacol. 52(5). 501-509 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] M. Higuchi, K.Yanai, N.Okamura, K.Meguro, H.Arai, M.Itoh, R.Iwata, T.Ido, T.Watanabe, and H.Sasaki: "Histamine H1 receptors in patients with Alzheimer's disease assessed by position emission tomography (PET)"Neuroscience 99. 721-729 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Takehiko Watanabe, Henk Timmermann and Kazuhiko Yanai: "(Eds)Histamine Research in the new Millennium"Elsevire Science B.V. Amsterdam. 1-521 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] J.I.Mobarakeh, et al.: "Improgan antinociception dosenot require newronal histamine or histamine receptors"Brain Research. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] L.S.Zhang et al.: "Effects of endogenous histamine on seizure development of pentylenete trazule-induced kindling in rats"Pharmacology. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Z.Chen, et al.: "Chemical kindling induced by pentylene in histamine H_1 recepter gene knockout mice (H_1KO), HDC^<-/->, and mast cell-deficient mice"Brain Research. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Y.Funaki, et al.: "Evaluation of the binding characteristics of [5-^<11>C-methoxy] donepezil in the rat brain for in vivo visualization of acetylcholinesteras"Journal of Pharmacological Sciences. 91(2). 105-112 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] S.Sakurada, et al.: "In trathecal histamine induces spinally-mediated behavioral responses though tachykinin NK_1 receptors"Pharmacol.Biochem.Behav.. 74. 487-493 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] J.I.Mobarakeh, et al.: "Enhanced antinociception by in trathecally-administered mcrphive in histamine H_1 receptor gene knockout mice"Neuropharmacology. 42(8). 271-280 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] J.I.Mobarakeh, K.Yanai et al.: "Enhanced antinocicoption by intrathecally-administerel morphine in his taminak H,receptor gene knockout micl"Neuro pharmacology. in press. (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] R.Iwata, K.Yanai, et al.: "A combined loop-SPE method for the automated proportion of["C] doxepin"J.Labelled Cpd. Radiopharm. 45. 271-280 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] M.Tagawa, M.Kano, et al.: "Differential cognitive effects of ebostine and d-chlorpheniramine in healthy subjects"Bn. J.Clin. Pharmacol. in press. (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] M.Tagawa, M.Kano, et al.: "Newoimazing of histamine H,recoptor occupancy in human brain, by positron emission tomography"Bn. J.Clin. Pharmacol. 52(5). 501-509 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] M.Endou, K.Yanai, et al.: "Food-deprived activity stress decreased the activity of the histaminergic neuron system in rats"Brain Research. 891. 32-41 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] R.Iwata, K.Yanai, et al.: "A simple loop method for the automated preparation of ["C]raclopride from ["C] methyl triflate"Applied Radiation Isotopes. 55. 17-22 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Takahiko Watanabe, Henk Timmerman, Kazuhiko Yanai: "Histamine Research in the New Millennium"Amsterdam, Elsevier Science B.V. 521 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] M.Endou, et al.: "Food-deprived activity stress decreased the activity of the histaminergic neuron system in rats."Brain Res.. (In press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] K.Yanai, et al.: "Histamine H_1 receptor-mediated inhibition of pottassium-evoked release of"Behavioral Brain Res.. (In press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] J.I.Moluarakeh et al.: "Role of histamine H_1 receptor in pair perception : A study of the gene knockout mice."Eur.J.Pharmacol.. 391. 81-89 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] M.Izumizahi et al.: "Lack of temperature-induced polypnea in histamine H_1 receptor-deficient mice."Neurosci.Lett. 284. 139-142 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] R.Iwata et al.: "A simple loop method for the antomated preparation of [^<11>C] naclopride from [^<11>C] methyl triflate"Applied Radiation Isotopes. 55. 23-28 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] R.Iwata et al.: "Synthesis of 3-[1H-imidazol-4yl] propyl-4-[^<18>F] fluorobenzyl ether ([^<18>F] fluoroproxyfan) : A potential radioligand for imaging"J.Labelled Compd.Radiopharm.. 43. 873-882 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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