動物PETによる脳機能分子イメージング：基礎研究から創薬研究へ

Molecular imaging of brain function with animal PET：Applications from basic research to drug development

生体機能を司る様々な生体内分子に特異的なポジトロン標識化合物の生体内分布・動態から，非侵襲的に生体機能を画像化・定量化できる分子イメージング法であるPET（positron emission tomography）は，実験動物を対象にした基礎研究からヒトを対象にした臨床研究まで，広範囲に応用されている。近年，膨大な時間と開発費用を要する医薬品開発の効率化のため，このPETの優れた特性を利用しようという試みが10年以上前から欧米の多くの医薬品会社でなされてきており，国内においてもようやくここ2，3年間でかなり広がってきている。開発中の医薬品の候補化合物をC-11，F-18等のポジトロン核種で標識して投与することで，その生体内動態・分布・代謝を観察できるだけでなく，生体内分子ターゲットを共有する既存の標識化合物との相互作用を計測することで，従来の血中濃度計測からだけではわからなかった作用部位での占有率と，その経時変化を計測することが可能となり，より少ない副作用でより高い効果を示す用量設定も可能となると期待される。本稿では，筆者らの基礎的な脳機能研究およびそれに基づいたパーキンソン病・認知症・うつ病・統合失調症に関与する，中枢作動薬・遺伝子治療の前臨床評価実験における動物PET研究の実例について紹介する。

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.