NEW SEROTONIN TRANSPORTER IMAGING AGENTS BY DESIGN

5-羟色胺转运体(SERT)是一种存在于中枢神经系统5-羟色胺(5-HT)神经元突触前终末的完整膜蛋白。SERT负责神经元放电后5-羟色胺从突触间隙中的清除。SERT功能的异常和/或脑内SERT受体密度的变化与各种神经和精神健康疾病有关。为了通过对活体大脑的功能成像研究来量化SERT的变化，一项全面的努力涉及到必要的放射性示踪剂的产生。仍然迫切需要发现新的SERT放射性配体。这项更新建议的目的是确定那些基于喹帕嗪的配体的身份，这些配体可能作为5-羟色胺转运体的正电子发射断层扫描(PET)动态脑显像剂。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：L)非放射性取代喹啉配体的化学合成；2)利用大鼠组织进行体外药理学评估；3)形成放射性标记的配体形式(氚以及碳-11和氟-18变体)；4)用大鼠模型评价放射性示踪剂的体内和体外分布；以及5)调查代谢分布。通过这些研究，我们将能够判断所选择的含有β发射标记的喹帕嗪配体是否具有作为未来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.