Selective Imaging Agents for the 5HT2c Receptor

描述（由申请人提供）：5-羟色胺受体亚型2c（5 HT 2c）在整个中枢神经系统（CNS）中以高丰度表达，并已被鉴定为治疗肥胖、药物滥用、抑郁、焦虑、精神分裂症和帕金森病的靶点。然而，由于无法准确定量CNS中5 HT 2c受体密度和功能，5 HT 2c受体系统异常与这些疾病之间的直接联系已被证明难以建立。仅存在几种体外探测5 HT 2c受体的方法，其中没有一种能够在体内定量5 HT 2c受体。因此，在体内可视化5 HT 2c受体的技术的发展代表了理解血清素系统的正常功能和病理生理学的关键一步。此外，这些技术将加速发现选择性与5 HT 2c受体相互作用的小分子治疗剂。为神经科学研究和药物发现提供成像工具，我们将开发用于正电子发射断层扫描（PET）的放射性示踪剂，可以提供有关5 HT 2c受体系统的分子水平信息。我们将通过用碳-11标记两种有效的选择性5 HT 2c激动剂WAY-163909和戊卡色林来实现这一目标。根据我们的初步数据，这些化合物可能提供大脑中5 HT 2c受体的化学特异性图谱。这项研究的成果将是一种用于体内5 HT 2c受体成像的新技术，可用于临床前和人体研究，以建立5 HT 2c生理学与脑部疾病之间的关系。

DESCRIPTION (provided by applicant): The serotonin receptor subtype 2c (5HT2c) is expressed in high abundance throughout the central nervous system (CNS) and has been identified as a target for the treatment of obesity, drug abuse, depression, anxiety, schizophrenia, and Parkinson's disease. A direct link between 5HT2c receptor system abnormalities and these diseases has proven difficult to establish, however, due to an inability to accurately quantify 5HT2c receptor density and function in the CNS. There exist only a few methods for probing 5HT2c receptors in vitro, none of which are capable of quantifying 5HT2c receptors in vivo. Thus, the development of techniques for visualizing 5HT2c receptors in vivo represents a key step in understanding both the normal function and pathophysiology of the serotonin system. Moreover, these techniques will accelerate the discovery of small molecule therapeutics that selectively interacts with the 5HT2c receptor. To provide an imaging tool for neuroscience research and drug discovery, we will develop radiotracers for positron emission tomography (PET) that can provide molecular-level information about the 5HT2c receptor system. We will accomplish this goal by labeling two potent and selective 5HT2c agonists, WAY-163909 and vabicaserin, with carbon-11. Based on our preliminary data, these compounds may provide a chemically specific map of 5HT2c receptors in the brain. The outcome of this research will be a new technology for imaging 5HT2c receptors in vivo that can be used in both preclinical and human research to establish relationships between 5HT2c physiology and brain diseases.