PET Imaging Agents for 5-HT2C Receptors

5-HT2C 受体 PET 显像剂

基本信息

批准号：
9193103
负责人：
Mark Myron Goodman
金额：
$ 23.4万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9193103
关键词：
Affinity Agonist Animal Model Anxiety Area Autopsy Basic Science Binding Biodistribution Biological Assay Blood - brain barrier anatomy Brain Brain Diseases Carbon Central Nervous System Diseases Cerebellum Characteristics Chemical Structure Chemicals Clinical Research Data Disease Dopamine Receptor Drug abuse Equilibrium Evaluation Feeding behaviors Functional disorder Future G-Protein-Coupled Receptors Glutamates Image In Vitro Indenes Indoles Investigation Kinetics Label Lead Ligands Macaca mulatta Measurement Measures Mediating Mental Depression Mental disorders Methods Molecular National Institute of Mental Health Neuraxis Neurosciences Neurosecretory Systems Obesity Organ Parkinson Disease Pathologic Pharmacology Physiology Positron-Emission Tomography Preclinical Drug Evaluation Process Property Psychotropic Drugs Publishing Radioactive Radioactivity Radiolabeled Regulation Reporting Reproducibility Rest Role Schizophrenia Serotonin Serotonin Receptor 5-HT2C Sprague-Dawley Rats Structure Structure-Activity Relationship Surface System Testing Therapeutic Time Tissues Tracer base density design dopaminergic neuron functional status imaging agent imaging potential imaging study in vivo in vivo imaging interest lipophilicity methyl group microPET nervous system disorder neurobehavioral nonhuman primate novel obesity treatment programs public health relevance radiochemical radioligand radiotracer serotonin receptor tool treatment strategy uptake

项目摘要

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.

描述（由适用提供）：5-羟色胺5-HT2C受体（5-HT2CR）基本上在整个中枢神经系统（CNS）中表达，并且参与了多种神经内分泌和神经性神经行为过程。来自动物模型，验尸组织和分子神经科学研究的证据表明，在许多重要的神经系统和精神疾病中隐含了5-HT2CR的功能障碍，并且5-HT2CR已被确定为治疗肥胖，抑郁，焦虑症，药物滥用，药物滥用，精神分裂症和帕克森病的靶标。未满足的需求是我们无法通过使用正电子发射断层扫描（PET）准确地量化5-HT2CR密度和在体内的功能状态来建立5-HT2CR生理和脑部疾病之间的直接关系，因为没有选择性和特定的PET放射性障碍物或特定的PET放射性激动剂或可用于5-HT2CR的动力学。该提案的核心目的是开发具有PET的碳和物理性质的碳-11 5-HT2CR-特异性放射性拮抗剂，用于体内成像研究。该提案的中心假设是，标记为双吡啶基 - 卡马氨基偶治烷基衍生物的碳11将以高度特异性和敏感的方式绘制5-HT2C的活性和静止状态。该假设基于最近发表的报告和我们关于潜在和选择性5-HT2CR拮抗剂Bispyridyl-Carbamoylindoles的优秀体外结合谱的初步发现。中央假设将通过完成以下特定目的来检验：1。合成和体外表征双吡啶基 - 卡马贝酰吲哚衍生物。 2。开发候选5-HT2CR配体拮抗剂的放射性标记方法。 3。确定放射标记的候选化合物是否会越过血脑屏障和Sprague-Dawley大鼠的体内动力学生物分布足以容纳5-HT2CR的优质PET成像。 4。确定铅候选宠物配体是否显示出非人类隐私大脑中5-HT2CR密度体内定量的分布和动力学特性。