Novel agonist tracers for PET imaging of kappa opioid receptors

用于 kappa 阿片受体 PET 成像的新型激动剂示踪剂

基本信息

批准号：
8899631
负责人：
YIYUN HENRY HUANG
金额：
$ 68.46万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-11 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8899631
关键词：
Addictive Behavior Affinity Agonist Alcoholism Alzheimer&apos s Disease Anxiety Applications Grants Benchmarking Binding Biological Assay Biological Markers Biomedical Research Brain Brain Diseases Brain region Cocaine Collection Communities Development Disease Drug Kinetics Evaluation Evaluation Studies Functional disorder Goals Human Image In Vitro Investigation Kinetics Label Lead Libraries Ligands Macaca mulatta Measurement Measures Mental Depression Mental disorders Mood Disorders Opioid Receptor Opioid Receptor Binding Performance Pharmaceutical Chemistry Phase Phased Innovation Awards Plasma Positron-Emission Tomography Primates Property Psychostimulant dependence Radioisotopes Radiolabeled Regulation Relative (related person)Reproducibility Research Signal Transduction Specificity System Testing Time Tissues Tracer Validation addiction base bioimaging cohort experience human subject imaging agent improved in vitro Assay in vivo insight interest lipophilicity neuropsychiatry nonhuman primate novel pre-clinical radiotracer receptor receptor density receptor expression research study screening stress related disorder uptake validation studies

项目摘要

DESCRIPTION (provided by applicant): The kappa opioid receptors (KORs) have been implicated in a number of psychiatric disorders including depression and related mood disorders, anxiety and stress-related disorders, addictions such as cocaine and other psychostimulant dependence, alcoholism, and Alzheimer's disease. The availability of PET imaging agents will provide non-invasive biomarkers to interrogate the KOR and gain insights into the function and dysfunction of this receptor system in the aforementioned disorders. Until recently there were no validated PET radiotracers to image KOR in humans, although radiotracers for other opioid receptor subtypes have been available for some time. In the last year we evaluated in humans two KOR ligands, one agonist and one antagonist, as PET tracers. The antagonist tracer, [11C]LY2795050, proves to be suitable for imaging and quantifying KOR in the human brain. However, the agonist tracer, [11C]GR103545, is not ideal, due to its slow tissue kinetics. The validation of [11C]LY2795050 marks the first time a KOR-selective tracer is available for use in humans. In this combined R21/R33 Phased Innovation Award application, we propose to build upon our expertise and experience in the development and evaluation of KOR PET tracers, and to synthesize, evaluate and validate two C-11 and/or F-18 labeled KOR agonist radiotracers for PET imaging studies in humans. Specifically, in the R21 phase of investigation we will implement a medicinal chemistry discovery, in vitro binding and functional assays, and in vivo PET imaging screening evaluation of candidate agonist tracers in non-human primates to critically appraise and select two C-11 and/or F-18 labeled tracers (and ideally, one C- 11, and one F-18 labeled tracer) for progressing to the R33 phase of comprehensive tracer evaluation and validation studies. In the R33 phase of investigation, the R21 selected tracers will undergo first a comprehensive evaluation in non-human primates to confirm in vivo binding specificity and selectivity, and subsequent quantitative PET imaging studies in humans to quantify regional specific binding signals, to assess the reproducibility of binding parameters and to determine non-displaceable volume of distribution. The ultimate goal is to provide the PET imaging community with a pair of agonist-antagonist radiotracers for the kappa opioid receptors. The development, and successful deployment of such an optimal, effective agonist-antagonist imaging tracer pair will enable, for the first time, the in vivo investigation of not only KOR expression, but also its functional state, in a variety of neuropsychiatric disorders and addictive conditions.

描述（由申请人提供）：Kappa阿片受体（KORS）与许多精神疾病有关，包括抑郁症和相关情绪障碍，焦虑和与压力有关的疾病，可卡因和其他精神刺激依赖性，酒精中毒和阿尔茨海默氏病。 PET成像剂的可用性将提供非侵入性生物标志物来询问KOR并获得对该受体系统在上述疾病中的功能和功能障碍的见解。直到最近，还没有经过验证的PET放射性示例来形象人类的Kor，尽管其他阿片类药物亚型的放射性示例已有一段时间。去年，我们在人类中评估了两个kor配体，一个激动剂和一名对手，作为宠物示踪剂。拮抗剂示踪剂[11C] LY2795050被证明适用于在人脑中成像和量化Kor。然而，由于其缓慢的组织动力学，激动剂示踪剂[11C] GR103545并不理想。 [11C] LY2795050的验证标志着第一次可在人类中使用KOR选择性示踪剂。在此组合的R21/R33分阶段创新奖应用程序中，我们建议以我们在Kor Pet示踪剂的开发和评估方面的专业知识和经验，并合成，评估和验证两个C-11和/或F-18标记的Kor Agonist Radiotracers在人类中进行宠物成像研究。具体而言，在R21调查阶段，我们将实施药物化学发现，体外结合和功能测定，以及在非人类灵长类动物中候选激动剂示踪剂的体内成像筛选评估，以认真评估并选择了两个C-11和/或选择了两个C-11和/或F-18标记的示踪剂（以及一个c-11 and c-11和One c-11 f acter and c-11，and One c-11，and One f acter and c-11 f ins and c-11 f ins and c-11 f ins for tab and c-11 f in and c-11 and f race and One c-8。全面的示踪剂评估和验证研究。在R33的研究阶段，R21选定的示踪剂将首先进行非人类灵长类动物的全面评估，以确认人类中人类中的体内结合特异性和选择性，并随后在人类中进行定量PET成像研究，以量化区域特异性结合信号，以评估结合参数的可重复性和确定不可置换量的分布的可重复性。最终目标是为宠物成像群落提供一对kappa阿片受体的激动剂 - 抗抗激射剂。这种最佳，有效的激动剂抗成像示踪剂对的开发和成功的部署将首次实现对KOR表达的体内研究，而且还可以在各种神经精神疾病和成瘾性疾病中对其功能状态进行研究。