Selective Imaging Agents for the 5HT2c Receptor

5HT2c 受体的选择性显像剂

• 批准号: 8190951
• 负责人: Jacob M. Hooker
• 金额: $ 26.19万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-20 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8190951
• 关键词: Age; Agonist; Anxiety; Area; Autoradiography; Behavioral; Benzodiazepines; Binding; Biodistribution; Biological Assay; Brain; Brain Diseases; Carbon; Cognitive; Cyclization; Data; Development; Diagnosis; Disease; Drug Addiction; Drug Kinetics; Drug abuse; Exhibits; Female; Formaldehyde; Functional disorder; Goals; Health; Human; Image; Imaging Device; Imaging technology; In Vitro; Kinetics; Knowledge; Label; Lead; Life; Ligands; Link; Maps; Mediator of activation protein; Mental Depression; Mental disorders; Metabolic; Metabolism; Methods; Modeling; Molecular; Neuraxis; Neurosciences Research; Neurotransmitters; Obesity; Organ; Outcomes Research; Papio; Papio anubis; Parkinson Disease; Pathology; Pharmaceutical Preparations; Physiological; Physiology; Plasma; Positioning Attribute; Positron-Emission Tomography; Prevalence; Quality Control; Radioactivity; Radiolabeled; Reaction; Reference Standards; Regulation; Research; Resolution; Rodent; Rodent Model; Scanning; Schizophrenia; Serotonin; Serotonin Receptor 5-HT2C; Specificity; System; Techniques; Testing; Therapeutic; Variant; base; dosimetry; drug discovery; enantiomer; human disease; imaging modality; in vivo; method development; nervous system disorder; neurophysiology; new technology; nonhuman primate; novel; obesity treatment; pre-clinical; radiotracer; rapid technique; receptor; receptor density; receptor function; serotonin receptor; serotonin transporter; sex; small molecule; technique development; tool

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. PUBLIC HEALTH RELEVANCE: The serotonin 2c receptor subtype (5HT2c) is expressed in high abundance in the human brain and has been proposed as a target for the treatment of obesity, drug abuse, depression, anxiety, schizophrenia, and Parkinson's disease. However, direct links between these diseases and 5HT2c receptor abnormalities have been difficult to form due to a lack of tools for determining 5HT2c receptor concentration and activation. We propose to develop the first in vivo imaging agent for directly probing and quantifying 5HT2c receptors using positron emission tomography (PET). This will accelerate 5HT2c research and the discovery of 5HT2c therapeutics, which may be used to treat human brain diseases.

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成像5 HT 2c受体的新技术，可用于临床前和人类研究，以建立5 HT 2c生理学和脑疾病之间的关系。 公共卫生关系：5-羟色胺2c受体亚型（5 HT 2c）在人脑中以高丰度表达，并且已被提议作为治疗肥胖、药物滥用、抑郁症、焦虑症、精神分裂症和帕金森病的靶点。然而，由于缺乏用于确定5 HT 2c受体浓度和活化的工具，这些疾病和5 HT 2c受体异常之间的直接联系难以形成。我们建议开发第一种使用正电子发射断层扫描（PET）直接探测和定量5 HT 2c受体的体内成像剂。这将加速5 HT 2c研究和5 HT 2c疗法的发现，这些疗法可能用于治疗人类大脑疾病。