Selective Imaging Agents for the 5HT2c Receptor

描述(申请人提供)：5-羟色胺受体亚型2c(5HT2c)在整个中枢神经系统(CNS)中大量表达，已被确定为治疗肥胖症、药物滥用、抑郁症、焦虑、精神分裂症和帕金森病的靶标。然而，由于无法准确量化中枢神经系统中5HT2c受体的密度和功能，5HT2c受体系统异常与这些疾病之间的直接联系已被证明是困难的。目前只有几种体外检测5HT2c受体的方法，没有一种方法能够在体内定量检测5HT2c受体。因此，体内5HT2c受体可视化技术的发展是理解5-羟色胺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地与5HT2c受体相互作用的小分子疗法。为了为神经科学研究和药物开发提供成像工具，我们将开发正电子发射断层扫描(PET)的放射性示踪剂，它可以提供关于5HT2c受体系统的分子水平信息。我们将通过用碳-11标记两种有效和选择性的5HT2c激动剂Way-163909和vabicaserin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了大脑中5HT2c受体的化学特异性图谱。这项研究的结果将是一种在体内成像5HT2c受体的新技术，可用于临床前和人类研究，以建立5HT2c生理和脑疾病之间的关系。

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.