Kappa receptor selective PET ligands

Kappa 受体选择性 PET 配体

• 批准号: 6553029
• 负责人: DAH-REN HWANG
• 金额: $ 14.72万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6553029
• 关键词: baboons; brain; clinical research; dynorphins; inhibitor /antagonist; laboratory rat; method development; neurotransmitters; opioid receptor; radiotracer; receptor binding; stimulant /agonist

DESCRIPTION (provided by applicant): Neuroreceptor imaging techniques using positron emission tomography allow the in vivo investigation of the neurotransmitter systems in psychiatric disease. As a result, radioligand imaging can provide direction for targeted treatment strategies. This is of critical importance in developing future pharmacotherapy for substance abuse. Both preclinical and clinical studies indicate that the "direct pathway" plays a critical role in relapse. The direct pathway consists of the GABAergic neurons of the striatum that project back to the substantial nigra/VTA, and which contain the D1 receptor and dynorphin. We have currently begun studies in cocaine dependence with a D1radioligand. Therefore the goal oft his application is the development of a radioligand for the kappa receptor, which can be employed in future studies of substance dependence. In the R21 portion of this application, we propose to develop both an agonist (GR103545) and antagonist (JDTic) radiotracer, as well as their analogs, for the kappa receptor. The development of these radiotracers will begin with the optimization of their synthesis, in order to ensure the most effective and reliable chemistry. These compounds will be evaluated in vitro in order to measure their affinity for the receptor and to establish their selectivity for the kappa receptor. Those ligands shown to have a high affinity and selectivity will then be evaluated in vivo in biodistribtuion studies in rodents, followed by studies in non-human primates. The studies in baboons will be used to establish the selectivity for the kappa receptor in vivo, the susceptibility of the radioligand to endogenous dynorphin, and to develop the imaging analysis of the radioligands. The candidate radioligands that meet the criteria outlined in the milestones will be chosen for the R33 portion of this application, which includes toxicology studies and test/retest studies in healthy human volunteers. The studies in human subjects will be performed in order to establish the selectivity for the kappa receptor in humans and to determine optimal scanning protocol. At the end of the award period, we expect to have developed both a kappa agonist and antagonist, which will be available for a wide range of research centers.

描述（由申请人提供）：使用正电子发射断层扫描的神经受体成像技术允许对精神病中神经递质系统进行体内研究。结果，放射性成像可以为有针对性的治疗策略提供方向。这对于开发未来的药物滥用药物疗法至关重要。临床前研究和临床研究都表明，“直接途径”在复发中起着至关重要的作用。直接途径由纹状体的GABA能神经元组成，该神经元将其投射回实质性的NIGRA/VTA，并包含D1受体和驱体。我们目前已经开始对可卡因依赖性进行研究。因此，他的应用的目标是开发用于Kappa受体的放射性物体，这可以在未来的物质依赖性研究中使用。 在本应用的R21部分中，我们建议为Kappa受体开发激动剂（GR103545）和拮抗剂（JDTIC）radiotracer及其类似物。这些放射性示踪剂的发展将从其合成的优化开始，以确保最有效，最可靠的化学。这些化合物将在体外进行评估，以测量其对受体的亲和力并确定对Kappa受体的选择性。这些配体显示具有高亲和力，然后将在啮齿动物的生物分布研究中对体内进行评估，然后在非人类灵长类动物中进行研究。狒狒的研究将用于建立体内喀巴受体的选择性，放射性物体对内源性驱指的敏感性，并开发对放射性体的成像分析。 符合里程碑中概述的标准的候选放射线将被选为本应用的R33部分，其中包括毒理学研究和健康人类志愿者中的测试/重测研究。将对人类受试者进行研究，以确定人类中喀巴受体的选择性并确定最佳扫描方案。在奖励期结束时，我们预计将开发出Kappa激动剂和对手，这将适用于广泛的研究中心。