Division of Nuclear Medicine, Department of Radiology , University of Michigan Medical School , Ann Arbor , Michigan 48109 , United States.
ACS Chem Neurosci. 2019 Jan 16;10(1):25-29. doi: 10.1021/acschemneuro.8b00429. Epub 2018 Sep 10.
Positron emission tomography (PET) studies of the monoamine neurotransmitter systems in the human brain employ a variety of radiotracers targeting the many receptors, transporters, and enzymes present in monoaminergic neurons. One of these is the vesicular monoamine transporter 2 (VMAT2), the protein responsible for the energy-dependent accumulation of monoamines into synaptic vesicles. The development of in vivo imaging radiotracers for VMAT2 is a story of starting with a well-characterized clinically used drug (tetrabenazine) which had a pharmacologically active metabolite: that metabolite that was in stepwise fashion refined and modified to provide both carbon-11 and fluorine-18 labeled VMAT2 radiotracers that are now used for human PET studies of neurodegenerative and psychiatric diseases. The design approach taken, which involved understanding the metabolism of the radiotracers and identification of the optimal ligand stereochemistry, are representative of important steps in the general concepts behind successful in vivo radiotracer design for brain imaging agents.
正电子发射断层扫描（PET）研究人类大脑中的单胺神经递质系统，采用了多种放射性示踪剂来靶向单胺能神经元中的许多受体、转运体和酶。其中之一是囊泡单胺转运体 2（VMAT2），它负责单胺类物质在能量依赖的情况下被摄取到突触小泡中。VMAT2 体内成像放射性示踪剂的开发，是从一种特征明确的临床应用药物（丙戊茶碱）开始的，该药物具有药理活性代谢物：逐步对该代谢物进行精制和修饰，提供了碳-11 和氟-18 标记的 VMAT2 放射性示踪剂，现在用于人类 PET 研究神经退行性和精神疾病。所采用的设计方法涉及到对放射性示踪剂代谢的理解和最佳配体立体化学的鉴定，这代表了成功设计用于脑成像的体内放射性示踪剂的一般概念背后的重要步骤。
