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

• 批准号: 8318066
• 负责人: YIYUN HENRY HUANG
• 金额: $ 28.14万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-11 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8318066
• 关键词: Addictive Behavior; Affinity; Agonist; Alcoholism; Alzheimer' 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; 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; Screening procedure; Signal Transduction; Specificity; System; Testing; Time; Tissues; Tracer; Validation; addiction; base; bioimaging; cohort; experience; human subject; improved; in vitro Assay; in vivo; insight; interest; kappa opioid receptors; lipophilicity; neuropsychiatry; nonhuman primate; novel; pre-clinical; radiotracer; receptor; receptor density; receptor expression; research study; stress related disorder; uptake; validation studies

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(申请人提供)：kappa阿片受体(Kors)与许多精神疾病有关，包括抑郁症和相关的情绪障碍、焦虑和压力相关的障碍、成瘾(如可卡因和其他精神刺激性依赖)、酒精中毒和阿尔茨海默病。PET显像剂的问世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。尽管其他阿片受体亚型的放射性示踪剂已经存在一段时间了，但直到最近还没有有效的PET放射性示踪剂来对人类的KOR进行成像。去年，我们在人体上评估了两种KOR配体，一种是激动剂，一种是拮抗剂，作为PET示踪剂。拮抗剂示踪剂[11C]LY2795050被证明适合于对人脑中的KOR进行成像和定量。然而，激动剂示踪剂[11C]GR103545并不理想，因为它的组织动力学较慢。[11C]LY2795050的验证标志着KOR选择性示踪剂首次可用于人类。在这份R21/R33阶段性创新奖的联合申请中，我们建议以我们在开发和评估KOR PET示踪剂方面的专业知识和经验为基础，合成、评估和验证两种用于人体PET成像研究的C-11和/或F-18标记的KOR激动剂放射性示踪剂。具体地说，在R21研究阶段，我们将对非人类灵长类动物的候选激动剂示踪剂进行药物化学发现、体外结合和功能分析以及体内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，选定的R21示踪剂将首先在非人类灵长类动物中进行全面评估，以确认体内结合的特异性和选择性，然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，评估结合参数的重复性，并确定不可移位的分布体积。最终目标是为PET成像界提供一对kappa阿片受体的激动剂-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能够在体内不仅研究KOR的表达，而且还研究其在各种神经精神障碍和成瘾条件下的功能状态。

项目成果

Kinetic Modeling and Test-Retest Reproducibility of 11C-EKAP and 11C-FEKAP, Novel Agonist Radiotracers for PET Imaging of the κ-Opioid Receptor in Humans.

11C-EKAP 和 11C-FEKAP（用于人类 γ-阿片受体 PET 成像的新型激动剂放射性示踪剂）的动力学建模和重测重现性。

• DOI: 10.2967/jnumed.119.227694
• 发表时间: 2020
• 期刊: Journal of nuclear medicine : official publication, Society of Nuclear Medicine
• 作者: Naganawa,Mika;Li,Songye;Nabulsi,Nabeel;Lin,Shu-Fei;Labaree,David;Ropchan,Jim;Gao,Hong;Mei,Michael;Henry,Shannan;Matuskey,David;Carson,RichardE;Huang,Yiyun
• 通讯作者: Huang,Yiyun