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）：κ阿片受体（KOR）与许多精神疾病有关，包括抑郁症和相关情绪障碍、焦虑和压力相关疾病、可卡因和其他精神兴奋剂依赖等成瘾、酗酒和阿尔茨海默病疾病。 PET 显像剂的出现将提供非侵入性生物标志物来询问 KOR 并深入了解该受体系统在上述疾病中的功能和功能障碍。直到最近，还没有经过验证的 PET 放射性示踪剂可以对人体 KOR 进行成像，尽管其他阿片受体亚型的放射性示踪剂已经出现一段时间了。去年，我们在人体中评估了两种 KOR 配体（一种激动剂和一种拮抗剂）作为 PET 示踪剂。拮抗剂示踪剂 [11C]LY2795050 被证明适合对人脑中的 KOR 进行成像和定量。然而，激动剂示踪剂 [11C]GR103545 由于其组织动力学缓慢，并不理想。 [11C]LY2795050 的验证标志着 KOR 选择性示踪剂首次可用于人类。在此联合 R21/R33 阶段性创新奖申请中，我们建议利用我们在 KOR PET 示踪剂开发和评估方面的专业知识和经验，并合成、评估和验证两种 C-11 和/或 F-18 标记的 KOR 激动剂用于人体 PET 成像研究的放射性示踪剂。具体来说，在 R21 阶段的研究中，我们将对非人类灵长类动物中的候选激动剂示踪剂进行药物化学发现、体外结合和功能测定以及体内 PET 成像筛选评估，以严格评估和选择两种 C-11 和/或 F-18 标记示踪剂（理想情况下，一种 C-11 和一种 F-18 标记示踪剂），以进入全面示踪剂评估和验证研究的 R33 阶段。在R33研究阶段，R21选定的示踪剂将首先在非人类灵长类动物中进行全面评估，以确认体内结合特异性和选择性，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，以评估重现性结合参数并确定不可位移的分布体积。最终目标是为 PET 成像界提供一对 kappa 阿片受体激动剂-拮抗剂放射性示踪剂。这种最佳、有效的激动剂-拮抗剂成像示踪剂对的开发和成功部署将首次实现在各种神经精神疾病和成瘾中不仅可以体内研究 KOR 表达，还可以研究其功能状态。状况。