NEW SEROTONIN TRANSPORTER IMAGING AGENTS BY DESIGN

5-羟色胺转运蛋白（SERT）是在中枢神经系统5-羟色胺（5-HT）神经元突触前末端发现的一种完整的膜蛋白。SERT负责神经元放电后突触间隙中5-羟色胺的清除。SERT功能异常和/或脑内SERT受体密度变化与多种神经和精神健康障碍有关。为了通过对活脑的功能成像研究来量化SERT的变化，一项全面的努力已经涉及到产生必要的放射性示踪剂。对发现新的SERT无线电配体的强烈需求仍然存在。这是本更新建议的目的是确定那些喹帕嗪基配体的身份，这些配体可能作为正电子发射断层扫描（PET）动态脑显像剂的血清素转运体。这项工作将使用具有一系列特定目标的发现范式，其中包括：1)非放射性取代喹嘧啶配体的化学合成；2)利用大鼠组织对配体进行体外药理评价；3)放射性标记形式的配体（氚以及碳-11和氟-18变体）的形成；4)用大鼠模型对放射性示踪剂进行体内和体外评价，研究示踪剂的分布和结合谱；5)代谢倾向调查。通过这些研究，我们将能够判断是否选择喹帕嗪为基础的配体，其中包含β发射标签，具有作为前瞻性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.