NEW SEROTONIN TRANSPORTER IMAGING AGENTS BY DESIGN

5-羟色胺转运体（serotonin transporter，SERT）是中枢神经系统中5-羟色胺（serotonin，5-HT）神经元突触前末梢上的一种膜蛋白。SERT负责在神经元放电后从突触间隙清除5-HT。脑内SERT功能的缺失和/或SERT受体密度的变化与多种神经和精神健康障碍有关。在努力量化SERT的变化，通过使用活脑的功能成像研究，一个全面的努力涉及到所需的放射性示踪剂的产生。仍然强烈需要发现新的SERT放射性配体。这是更新建议的目的，以确定这些quipazine为基础的配体，可能作为正电子发射断层扫描（PET）的动态脑显像剂的5-羟色胺转运的身份。这项工作将采用一种发现范式，该范式具有一系列特定的目标，包括：1）化学合成非放射性取代的quipazine配体; 2）使用大鼠组织对配体进行体外药理学评估; 3）形成放射性标记形式的配体（氚以及碳-11和氟-18变体）; 4）用大鼠模型在体内和离体评估放射性示踪剂以研究示踪剂分布和结合概况;和5）调查代谢处置。通过这些调查，我们将能够判断是否选择quipazine为基础的配体，其中包含β发射标签，具有作为前瞻性的动态脑显像剂的价值。

The serotonin transporter (SERT) is an integral membrane protein found on pre-synaptic terminals of serotonin (5-HT) neurons in the central nervous system. The SERT is responsible for clearance of 5-HT from the synaptic cleft after neuronal firing. Abnormalities in SERT function and/or changes in SERT receptor densities within the brain have been implicated in a variety of neurological and mental health disorders. In an effort to quantify SERT changes through the use of functional imaging studies of living brain, a comprehensive effort has involved the generation of the requisite radiotracers. A strong need for the discovery of new SERT radioligands remains. It is the objective of this renewal proposal to ascertain the identity of those quipazine-based ligands which may serve as positron emission tomography (PET) dynamic brain imaging agents for the serotonin transporter. This effort will use a discovery paradigm constructed with a sequence of specific aims, which include: l) the chemical synthesis of non-radioactive substituted quipazine ligands; 2) the in vitro pharmacological assessments of the ligands using rat tissues; 3) the formation of radiolabeled forms of the ligands (tritium and also carbon-11 and fluorine-18 variants); 4) evaluation of the radiotracers both in vivo and ex vivo with rat models to study tracer distributions and binding profiles; and 5) surveys of metabolic dispositions. By these investigations we will be able to judge as to whether select quipazine-based ligands, which contain beta emitting labels, possess value as prospective dynamic brain imaging agents.