脳内コリン系神経の分子イメージング：分子設計から臨床応用まで

Molecular imaging of the cholinergic system in the brain

PETを用いた脳内コリン系神経の分子イメージングを目的として，静脈内投与後速やかに脳内に入り，アセチルコリンエステラーゼ（AChE）により加水分解された後，トラップされるアセチルコリン類似物質を何種類か分子デザインし，合成した。この中から最も優れた定量性を持つと考えられるトレーサを選択し，各脳部位の時間放射能曲線と動脈血入力関数を測定し，3コンパートメントモデルに基づき脳内AChE活性を健常者，アルツハイマー病患者，パーキンソン病患者において定量的に求めた。入力関数の測定を必要としない簡便な定量法も開発，検証した。本法は単に放射性物質により脳画像が得られるというだけでなく，その背景にある生化学的反応を定量的に評価できる真の分子イメージング法の1つと考えられた。

A method for quantitative measurement of brain acetylcholinesterase（AChE）activity in living human brain using positron emission tomography（PET）was developed for molecular imaging of the brain cholinergic system. We tested several radiolabeled lipophilic acetylcholine analogs（N-methylpiperidyl esters）, which readily crossed the blood-brain barrier, were hydrolyzed selectively by AChE, and then were trapped in the brain. Among them, N-［¹¹C］methylpiperidin-4-yl acetate（［¹¹C］MP4A）and propionate（［¹¹C］MP4P）were used as tracers for clinical PET studies. A three-compartment model, an arterial blood compartment and a cerebral tissue compartment comprising of two subcompartments representing unmetabolized and metabolized radiotracer, was applied. The plasma input function was obtained using thin-layer chromatography and an imaging phosphor plate system at frequent sampling intervals to catch the rapid metabolism of the tracer in the blood. Quantitative measurement of cerebral AChE activity was accomplished by fitting the time courses of cerebral radioactivity concentration measured by PET and the metabolite-corrected arterial plasma input function using a nonlinear least-squares fitting method. Normal control studies of subjects with a wide age range（24-89 years）showed no decrease in cerebral AChE activity with age, suggesting that the ascending cholinergic system was preserved in normal aging. Studies on patients with Alzheimer's disease demonstrated a widespread reduction ofAChE activity in the cerebral cortex（more profound in early-onset than late-onset Alzheimer's disease）. Parkinson's disease and progressive supranuclear palsy, clinically similar disorders, could be differentiated with［¹¹C］MP4A-PET studies. Simple methods without using arterial input function are also proposed. This study has demonstrated that quantitative evaluation of a certain biochemical process in the living human brain is possible by using proper radioactive compounds and measuring the input function accurately, and than applying an appropriate kinetic modeling. This method provides not only nuclear images that reflect AChE distribution but also quantitative measures of AChE activity, a cholinergic aspect of brain function, and, as a consequence, statistical comparisons of cholinergic brain function become possible among healthy and diseased subjects.