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The development for novel positron-labeled radiopharmaceuticals and their application to measurement of the cerebral functions

Research Project

Project/Area Number 11694234
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field 応用薬理学・医療系薬学
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) TASHIRO Manabu  TOHOKU UNIVERSITY SCHOOL OF MEDICINE, RESEARCH ASSOCIATE, 大学院・医学系研究科, 助手 (00333477)
ITOH Masatoshi  TOHOKU UNIVERSITY CYCLOTRON AND RADIOISOTOPE CENTER, PROFESSOR, サイクロトロンRIセンター, 教授 (00125501)
IWATA Ren  TOHOKU UNIVERSITY CYCLOTRON AND RADIOISOTOPE CENTER, ASSOCIATE PROFESSOR, 大学院・工学研究科, 助教授 (60143038)
Project Period (FY) 1999 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥19,480,000 (Direct Cost: ¥17,800,000、Indirect Cost: ¥1,680,000)
Fiscal Year 2001: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000)
Fiscal Year 2000: ¥5,600,000 (Direct Cost: ¥5,600,000)
Fiscal Year 1999: ¥6,600,000 (Direct Cost: ¥6,600,000)
KeywordsRadiopharmaceuticals / PET / receptor occupancy / cognitive function / cerebral blood flow / ligand-activation study / carbon-11 / fluorine-18 / Carbon-11(^<11>C) / carbon-11(^<11>C) / carbon-11(C^<11>) / fluorine-18(F^<18>) / histamine / 脳賦活試験 / H_2O^<15> / 眠気 / アルツハイマー病
Research Abstract

Positron emission tomography (PET) is a unique method to examine brain chemistry non-invasively in humans. Using PET techniques, specific neurochemical systems, such as dopaminergic and histaminergic neuronal systems, were measured in the living human brain. Specific ^<11>C- or ^<18>F-labelled radiotracers for selective labeling of several receptors were newly synthesized by new synthetic methods. 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 neurotransmitter release. As for pharmacological applications, we used PET techniques for evaluating sedative properties of antihistamines. Antihistamines are the efficacious drugs to be used for the symptomatic relief of allergic diseases. The safety issue of antihistamine … More s is of central importance because of their widespread use in current medical practice. PET was used to better understand the pharmacological effects of antihistamines on the central nervous system. The H1 receptor occupancy was examined in young male volunteers with [^<11>C]-doxepin (a potent H1 antagonist) after the oral or intravenous administration of antihistamines. In other studies, the cognitive performance was also measured tachistoscopically before and after taking antihistamines. The H1 receptor occupancy in the human frontal cortex caused by antihistamines is significantly correlated with the reported values of incidence of sleepiness in clinical trials, and the occupancy is well proportional to the impaired cognitive performance. To understand the brain mechanism of antihistamine-induced "sleepiness and impaired cognition", the regional cerebral blood flow (rCBF) during the task was measured using 3D-PET and H_2^<15>O before and after administration of d-chlorpheniramine. After its administration, the rCBF was significantly decreased on the bilateral middle temporal gyrus, midbrain and anterior cingulate. These findings suggest that H1 receptor blockade would be affected on the activity of the attention and cognitive system in the brain. Less

Report

(4 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • 1999 Annual Research Report
  • Research Products

    (44 results)

All Other

All Publications (44 results)

  • [Publications] J.I.Mobarakeh, Y.Yanai et al.: "Enhanced antinocieption by intra thecally-adminstersd morphine in histamine H, receptor gene knockout mice"Neuropharmacology. (in press). (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] R.Iwata, K.Yanai et al.: "A combined loop-SPE method for the automated preparation of [^<11>c]doxepin"J. Labelled Cpd. Radiopharm. 45. 271-280 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] M.Tagawa, K.Yanai et al.: "Neuroimaging of histamine H1-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
      2001 Final Research Report Summary
  • [Publications] M.Endou, K.Yanai et al.: "Food-deprived activity stress decreased the activity of the histaminergic neuron system in rats"Brain Research. 891. 501-509 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] M.Higuchi, K.Yanai et al.: "Histamine H1 receptors in patients with Alzheimers 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
      2001 Final Research Report Summary
  • [Publications] N.Okamura, K.Yanai et al.: "Functional neuroimaging of cognition impaired by a classical antihistamine, d-chlorpheniramine"Br. J. Pharmacol.. 129. 115-123 (2000)

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

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] I. Mobarakeh, S. Sakurada, T. Hayashi, T. Orito, K, Okuyama, T. Sakurada, A. Kuramasu, T. Watanabe, T. Watanabe, K. Yanai: "Enhanced antinociception by intrathecally-administered morphine in histamine H1 receptor gene knockout mice"Neuropharmacology. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] R. Iwata, C. Pascali, A. Bogni, K. Yanai. M. Kato, T. Ido, K. Ishiwata: "A combined loop-SPE method for the automated preparation of [^<11>C]doxepin"J. Labelled Cpd. Radiopharm. 45. 271-280 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] M. Tagawa, M. Kano, N. Okamura, M. Higuchi, M. Matsuda, Y. Mizuki, H. Arai, T. Fujii, S. Komemushi, M. Itoh, H. Sasaki, T. Watanabe, K. Yanai: "Differential cognitive effects of ebastine and d-chlorpheniramine in healthy subjects : Correlation between psychomotor performance and plasma concentration"Br. J. Clin, Pharmacol.. 53(3). 296-304 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] S. Sakurada, T. Orito, C. Sakurada, T. Sato, T. Hayashi, K. J. I. Mobarakeh, K. Yanai, K. Onodera, T. Watanabe, T. Sakurada: "Possible involvement of tachykinin NK1 and NMDA receptors in histamine-induccd hyperalgesia in mice"Eur. J. Pharmacol. 434. 29-34 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] S. Nishino, N. Fujiki, B. Ripley, E. Sakurai, M. Kato, T. Watanabe, E. Mignot, K. Yanai: "Decreased brain histamine contents in hypocretin/orexin receptor 2-mutated narcoleptic dogs"Neurosci. Lett.. 313. 125-128 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] M. Endou, K. Yanai, E. Sakurai, S. Fukudo, M. Hongo, T. Watanabe: "Food-deprived activity stress decreased the activity of the histaminergic neuron system in rats"Brain Res. 891. 32-41 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 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. Itoh, H. Sasaki, T. Watanabe, K. Yanai: "Neuroimaging of histamine H1-receptor occupancy in human brain by positron emission tomography (PET) : A comparative study of ebastine, a second-generation antihistamme, 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
      2001 Final Research Report Summary
  • [Publications] R. Iwata, C. Pascali, A. Bogni, Y. Miyake, K. Yanai, T. Ido: "A simple loop method for the automated preparation of [^<11>C]raclopride from [^<11>C]methyl triflate"Applied Radiation Isotopes. 55. 23-28 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] M. Higuchi, K. Yanai, N. Okamura, K. Meguro, H. Aral, M. Itoh, K. Iwata, T. Ido, T. Watanabe, H. Sasaki: "Histamine H1 receptors in patients with Alzheimer's disease assessed by positron emission tomography (PET)"Neuroscience. 99. 721-729 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] R. Iwata, G. Horvath, C. Pascali, A. Bogni, K. Yanai, Z. Kovacs, T. Ido: "Synthesis of 3-[1H-imidazol-4-yl]propyl4-[^<18>F]fluorobenzyl ether ([^<18>F]fluoroproxyfan) : A potential radioligand for imaging histamine H3 receptors"J. Labelled Compd. Radiopharm. 43. 873-882 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] M. Tagawa, M. Kano, N, Okamura, M. Itoh, E. Sakurai, T. Watanabe, K. Yanai: "Relationship between effects of alcohol on psychomotor performances and blood alcohol concentrations"Jap. J. Pharmacol.. 83. 253-260 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] N. Okamura, K. Yanai, M. Higuchi, J. Sakai, R. Iwata, T. Ido, H. Sasaki, T. Watanabe, M. Itoh: "Functional neuroimaging of cognition impaired by a classical antihistamine, d-chlorpheniramine"Br. J. Pharmacol.. 129. 115-123 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] R. Iwata, C. Pascali, A. Bongi, G. Horvath, Z. Kovacs, K. Yanai, T. Ido: "A new, convenient method for the preparation of 4-[^<18>F]fluorobenzyl halides"Appl. Radiat. Isot.. 52. 87-92 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] M. Izumizaki, M. Iwase, H. Kimura, K. Yanai, T. Watanabe, T. Watanabe, I. Homma: "Lack of temperature-induced polypnea in histamine H1 receptor-deficient mice"Neurosci. Lett.. 284(3). 139-142 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] J. I. Mobarakeh, S. Sakurada, S. Katsuyama, M. Kutsuwa, A. Kuramasu, Z. Y. Li, T. Watanabe, Y. Hashimoto, T. Watanabe, K. Yanai: "Role of histamine H_1 receptor in pain perception : A study of the receptor gene knockout mice"Eur. J. Pharmacol.. 391. 81-89 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] K. Yanai. N. Okamura, M. Tagawa, M. Itoh, T. Watanabe: "New findings in pharmacological effects induced by antihistamines : From PET studies to knockout mice"Clin Exp Allergy. 29 (Suppl 3). 29-36 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] T. Morimoto, Y. Yamamoto, J. I. Mobarakeh, K. Yanai, T. Watanabe, T. Watanabe, T. Watanabe, A. Yamatodani: "Involvement of the histaminergic system in leptin-induced suppression of food intake"Physiol. Behav.. Vol. 67(5). 679-683 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] H. Toyota, C. Ito, K. Yanai, M. Sato, T. Watanabe: "Histamine H1 receptor binding capacities in the amygdaloid kindled rat"J. Neurochem.. 72. 2177-2180 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] J.I.Mobarakeh, K.Yanai et al.: "Enhanced antinociception by intrathecally-administered morphine in histamine H1 receptor gene Knockout mil."Neuro pharmacology. (in Press).

    • Related Report
      2001 Annual Research Report
  • [Publications] R.Iwata, K.Yanai, et al.: "A combined loop-SPE method for the automated preparation of [^<11>C] doxepin"J. Labelled Cpd. Radiopharm. 45. 271-280 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] S.Nishino, K.Yanai, et al.: "Decreased brain histamine contents in hypocnetin/ovexin receptor 2-mutated narcoleptic dogs"Neurosci Lett.. 313. 125-128 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] M.Tagawa, K.Yanai, et al.: "Neuroimaging of histamine H1 receptor auipancy in human brain by positron emission tomography"Br. 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 neurou 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 [^<11>C] raclopride from [^<11>C] methyl triflate"Applied Radiation Isotopes. 55. 17-22 (2001)

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

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

    • Related Report
      2000 Annual Research Report
  • [Publications] M.Higuchi,K.Yanai et al.: "Histamine H, receptors in patient with Alzheimers disease assessed by positron emission tomography(PET)"Neuroscience. 99. 721-729 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] R.Iwata. et al.: "Synthesis of 3-[IH-imidazol-4-yl] mopyl4-[^<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
  • [Publications] N.Cbamura,K.Yanai et al.: "Functional neuroimaging of cognition impaired by a classical antihistamine, d-chlorpheniramine."Br.J.Pharmacol.. 129. 115-123 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] R.Iwata et al.: "A new-convenient method for the preparation of 4-[^<18>F] fluorobenzyl halides."Appl.Radiat.Isot.. 52. 87-92 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] K.Yanai et al.: "Histamine H_1 receptor-mediated inhibition of potassium-evoked release of 5-hydroxytryptamine from mice forebrains"Behavioral Brain Research. (in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] J.I.Mobarakeh et al.: "Role of histamine H_1 receptor in pain perception: A study of the receptor gene Knockout mice"European Journal of Pharmacology. (in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] N.Okamura et al.: "Functional neuroimaging of cognition inpaired by a classical antihistamine,d-chlor phenisamine"British Journal of Pharmacology. 129. 115-123 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] R.Iwata et al.: "A new convenient method for the preparation of 4-〔F^<18>〕 fluorobenzyl halides"Applied Radiation Isotopes. 52. 87-92 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] T.Morimoto et al.: "Involvement of the histaminergic system in leptin-induced suppression of food intake"Physiol. Behav.. 67. 679-683 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] H.Toyota et al.: "Histamine H_1 receptor binding capacities in the amygdaloid kindled rat"Journal of Neurochemistry. 72. 2177-2180 (1999)

    • Related Report
      1999 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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