PET Imaging Agents for 5-HT2C Receptors

 描述（由申请人提供）：5-羟色胺5-HT 2C受体（5-HT 2CR）在整个中枢神经系统（CNS）中大量表达，并参与多种神经内分泌和神经行为过程。来自动物模型、死后组织和分子神经科学研究的证据表明，5-HT 2CR的功能障碍与许多重要的神经和精神疾病有关，并且5-HT 2CR已被确定为治疗肥胖症、抑郁症、焦虑症、药物滥用、精神分裂症和帕金森病的靶点。未满足的需求是我们不能通过使用正电子发射断层扫描（PET）在体内准确定量5-HT 2CR密度和功能状态来建立5-HT 2CR生理学和脑疾病之间的直接关系，因为没有可用于5-HT 2CR的选择性和特异性PET放射性示踪剂激动剂或拮抗剂。该提案的中心目标是开发具有药理学和理化性质的碳-11 5-HT 2CR特异性放射性配体拮抗剂，用于PET体内成像研究。该提议的中心假设是碳-11标记的双吡啶基-氨基甲酰基吲哚衍生物将使得能够以高度特异性和灵敏度的方式映射5-HT 2C的活性和静息状态。这一假设是基于最近发表的报告和我们的初步研究结果的优秀的体外结合概况的有效和选择性的5-HT 2CR拮抗剂，双吡啶基-氨基甲酰吲哚。中心假设将通过完成以下具体目标进行检验：1.合成双吡啶基氨基甲酰吲哚衍生物并进行体外表征。2.建立5-HT 2CR配体拮抗剂的放射性标记方法。3.为了确定放射性标记的候选化合物是否会穿过血脑屏障，以及在Sprague-Dawley大鼠中的体内动力学生物分布是否足以用于5-HT 2CR的高质量PET成像。4.确定先导候选PET配体是否显示出有利的分布和动力学特性，用于非人灵长类动物脑中5-HT 2CR密度的体内定量。

 DESCRIPTION (provided by applicant): The serotonin 5-HT2C receptor (5-HT2CR) is abundantly expressed throughout the central nervous system (CNS), and is involved in a variety of neuroendocrine and neurobehavioral processes. Evidence from animal models, postmortem tissues, and molecular neuroscience studies suggests that dysfunction of 5-HT2CR has been implicated in a number of significant neurological and psychiatric disorders, and 5-HT2CR has been identified as a target for the treatment of obesity, depression, anxiety, drug abuse, schizophrenia and Parkinson's disease. The unmet need is our inability to establish a direct relationship between 5-HT2CR physiology and brain diseases by accurately quantifying 5-HT2CR density and functional status in vivo using Positron Emission Tomography (PET), because there are no selective and specific PET radiotracer agonists or antagonists available for 5-HT2CR. The central objective of this proposal is to develop a carbon-11 5-HT2CR- specific radioligand antagonist with pharmacological and physiochemical properties for in vivo imaging studies by PET. The central hypothesis of this proposal is that a carbon-11 labeled bispyridyl-carbamoylindole derivative will enable mapping of both active and the resting states of 5-HT2C in a highly specific and sensitive manner. This hypothesis is based upon recent published reports and our preliminary findings on the excellent in vitro binding profiles of potent and selective 5-HT2CR antagonists, bispyridyl-carbamoylindoles. The central hypothesis will be tested by completing the following specific aims: 1. To synthesize and in vitro characterize bispyridyl-carbamoylindole derivatives. 2. To develop radiolabeling methods for the candidate 5-HT2CR ligand antagonist. 3. To determine whether radiolabeled candidate compounds will cross the blood brain barrier and the in vivo kinetic biodistribution in Sprague-Dawley rats is sufficient for quality PET imaging of 5-HT2CR. 4. To determine whether the lead candidate PET ligands show favorable distribution and kinetic properties for in vivo quantification of 5-HT2CR density in the brain of non-human primates.