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Molecular imaging of brain function with animal PET:Applications from basic research to drug development Hideo Tsukada 1 1Central Research Laboratory, Hamamatsu Photonics K.K. Keyword: PET , 創薬 , 中枢作動薬 , 疾患動物モデル pp.959-965
Published Date 2005/12/10
DOI https://doi.org/10.11477/mf.1431100119
  • Abstract
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Positron emission tomography(PET)has widely been applied in the scientific fields of the basic research with experimental animals and the clinical studies subjecting human patients. PET can noninvasively image the biochemical and physiological information by determination of the distribution and kinetics of the target-specific ligands labeled with positron emitters.

 We demonstrated with high-resolution animal PET that the general physiological parameters of cerebral blood flow(CBF)and cerebral glucose metabolism(CMRglc), measured by[15O]H2O and[18F]FDG, respectively, were significantly lowered in aged monkey compared to young ones. In addition, more specific neuroreceptor binding activity and transporter capability were evaluated to show that muscarinic acetylcholine receptor measured by[11C]3-MPB, dopamine D1/D2 receptors and dopamine transporter measured by[11C]SCH23390,[11C]raclopride and[11C]β-CFT, serotonin 1A/2A and serotonin transporter measured by[11C]WAY100635,[11C]MDL100907 and[11C]McN5652, were significantly reduced in the aged monkeys. Of interest, we found that the physiological and pharmacological responses of neurotransmitter systems to molecular target-specific drugs were also altered by aging processes. CBF response to the vibrotactile stimulation given to the right hand was much smaller in aged monkeys than in young one, which might reflect the lowered muscarinic acetylcholine receptor binding in the cortical areas. In addition, the age-related impairment of CBF response was partially recovered by cholinesterase inhibitors. We demonstrated that aged monkeys provided impaired working memory along with the lowered muscarinic acetylcholine receptor binding, and the lowered working memory performance was improved by donepezil, a cholinesterase inhibitor. The activity of cholinesterase inhibition was assessed noninvasively with[11C]MP4A as well as with invasive microdialysis method, evidencing that[11C]MP4A was very useful labeled ligand to monitor the efficacy of cholinesterase inhibitor in the living brain. Chronic treatment of MK-801, a NMDA receptor inhibitor, induced the increased binding of[11C]NNC112 to prefrontal dopamine D1 receptors, but no alterations in[11C]FLB457 binding. The increased binding of[11C]NNC112 to D1 receptors was normalized by administration of acute nicotine in a dose-dependent manner. These results indicated that nicotine, in high tobacco smoking related doses, played an important role in modulation of abnormal prefrontal dopaminergic system induced by suppression of glutamatergic neuronal system, suggesting in part the higher smoking ratio in schizophrenic patients.

 In the present paper, our own experiences of animal PET studies for the basic research as well as drug development in preclinical stage will be discussed.


Copyright © 2005, Igaku-Shoin Ltd. All rights reserved.

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電子版ISSN 1882-1243 印刷版ISSN 0001-8724 医学書院

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