PET imaging of kappa opioid receptors: Tracer validation and sex/age effect study

kappa 阿片受体的 PET 成像：示踪剂验证和性别/年龄效应研究

• 批准号: 8604420
• 负责人: YIYUN HENRY HUANG
• 金额: $ 60.52万
• 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: 2011-04-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8604420
• 关键词: Addictive Behavior; Adverse effects; Affinity; Age; Agonist; Alcohol dependence; Alzheimer' s Disease; Anxiety; Applications Grants; Area; Binding; Biochemical Process; Biological Markers; Biomedical Research; Blood specimen; Brain; Brain Diseases; Carbon; Cocaine; Communities; Data; Dependence; Development; Disease; Dose; Enrollment; Evaluation; Event; Female; Functional disorder; Goals; Heroin; Human; Image; Image Analysis; Investigation; Kinetics; Life; MRI Scans; Measurement; Measures; Mental Depression; Mental disorders; Methodology; Methods; Modeling; Mood Disorders; Motion; Naltrexone; Nicotine Dependence; Opiates; Opioid; Opioid Receptor; Oral; Pharmaceutical Preparations; Pharmacotherapy; Play; Positron-Emission Tomography; Prevalence; Protocols documentation; Regulation; Reporting; Reproducibility; Research; Resolution; Role; Scanning; Sensory Receptors; Sex Characteristics; Specificity; Structure; Symptoms; System; Testing; Therapeutic; Time; Tissues; Tracer; Treatment Efficacy; Validation; Validity and Reliability; addiction; age difference; age effect; bioimaging; density; effective therapy; experience; human subject; in vivo; insight; kappa opioid receptors; male; mu opioid receptors; nervous system disorder; neuropsychiatry; non-invasive imaging; nonhuman primate; novel; novel therapeutics; public health relevance; radiotracer; receptor; receptor density; receptor expression; regional difference; research study; response; sex; stress related disorder; therapeutic development; therapy development; tool; treatment response

DESCRIPTION (provided by applicant): The kappa opioid receptors (KORs) have been implicated in a number of neuropsychiatric disorders including depression, anxiety and stress-related disorders, addictions, as well as Alzheimer's disease. The availability of validated PET imaging agents will provide non-invasive biomarker to investigate the KOR and gain insights into the function and dysfunction of this receptor in these disorders. Until recently there were no PET radiotracers for use in humans to image KOR, although tracers for other opioid receptors have been available. We are the first to have conducted the initial test of a pair of selective KOR agonist ([11C]GR103545) and antagonist ([11C]LY2795050) tracers in humans for the in vivo quantification of KORs. This is significant, as an antagonist tracer measures the total receptor availability, while an agonist tracer measures only the availability of receptors configured in the high affinity state, which is the functional, or active state. Therefore, the availability of an agonist/antagonist pair of PET tracers will, for the first time, allow the simultaneous assessment of both total KOR receptor expression, and, as importantly, the portion of KOR configured in its functional state, which may change in disease conditions. Building upon our initial human experience, the first major goal of this proposal is to establish the reliability and validity of [11C]GR103545 and [11C]LY2795050 as PET imaging agents for the quantification of KOR in humans. The validation and successful application of selective PET imaging agents for the KOR will have broad impact in the investigation and elucidation of the opioid system and the KORs, in gaining further understanding in the involvement of this receptor subtype in brain disorders, and in the development of novel therapeutics for a wide range of pathological conditions. Many psychiatric disorders, chief among them depression, anxiety and addictions, display strong sex differences in prevalence, time course, and/or treatment response. Understanding sex differences in neuroreceptor expression and function will provide insights into the biochemical processes of these disorders and inform treatment development of sex-specific pharmacotherapies. PET imaging is a powerful tool in this investigation, as it allows the investigation of receptor availability in the living human subjects. Therefore, the second major goal of this application is to use the validated KOR-selective PET tracers to investigate the effects of sex and age on the availability of total receptor, and the portion configured in the functional, high affinity state, in the living brain. We also will explore whether there is an age effect on KOR given that the regional densities of most receptors and transporters decrease with age. It is noteworthy, however, that 5 opioid receptor densities were shown to increase with age, and thus it may be possible that the regulation of opioid receptors is distinctly different from that of other receptor types. The investigation in this proposal will help provide answer to this question.

描述（由申请人提供）：κ阿片受体（KOR）与许多神经精神疾病有关，包括抑郁症、焦虑症和压力相关疾病、成瘾以及阿尔茨海默病。 经过验证的 PET 显像剂的出现将提供非侵入性生物标志物来研究 KOR 并深入了解该受体在这些疾病中的功能和功能障碍。 直到最近，尽管其他阿片受体的示踪剂已经可用，但还没有可用于人体对 KOR 进行成像的 PET 放射性示踪剂。 我们是第一个在人体中对一对选择性 KOR 激动剂 ([11C]GR103545) 和拮抗剂 ([11C]LY2795050) 示踪剂进行初步测试，以进行 KOR 体内定量的研究。 这很重要，因为拮抗剂示踪剂测量总受体可用性，而激动剂示踪剂仅测量配置为高亲和力状态（即功能或活性状态）的受体的可用性。 因此，激动剂/拮抗剂对 PET 示踪剂的出现将首次允许同时评估总 KOR 受体表达，并且同样重要的是，KOR 处于其功能状态的部分（可能会在疾病情况。 基于我们最初的人类经验，该提案的第一个主要目标是确定 [11C]GR103545 和 [11C]LY2795050 作为 PET 成像剂用于定量人类 KOR 的可靠性和有效性。 KOR 选择性 PET 显像剂的验证和成功应用将对阿片类药物系统和 KOR 的研究和阐明、进一步了解该受体亚型与脑部疾病的关系以及开发针对多种病理状况的新疗法。 许多精神疾病，其中主要是抑郁症、焦虑症和成瘾症，在患病率、时间进程和/或治疗反应方面表现出强烈的性别差异。 了解神经受体表达和功能的性别差异将有助于深入了解这些疾病的生化过程，并为性别特异性药物疗法的开发提供信息。 PET 成像是这项研究中的一个强大工具，因为它可以研究活体人类受试者中受体的可用性。 因此，该应用的第二个主要目标是使用经过验证的 KOR 选择性 PET 示踪剂来研究性别和年龄对活体大脑中总受体以及配置为功能性、高亲和力状态的部分的可用性的影响。 鉴于大多数受体和转运蛋白的区域密度随着年龄的增长而降低，我们还将探讨年龄对 KOR 是否有影响。 然而值得注意的是，5种阿片受体密度随着年龄的增长而增加，因此阿片受体的调节可能与其他受体类型明显不同。 本提案中的调查将有助于回答这个问题。

项目成果

PET imaging reveals sex differences in kappa opioid receptor availability in humans, in vivo.

PET 成像揭示了人类体内 kappa 阿片受体可用性的性别差异。

• 发表时间: 2016
• 期刊: American journal of nuclear medicine and molecular imaging
• 影响因子: 2.5
• 作者: Vijay,Aishwarya;Wang,Shuo;Worhunsky,Patrick;Zheng,Ming-Qiang;Nabulsi,Nabeel;Ropchan,Jim;Krishnan-Sarin,Suchitra;Huang,Yiyun;Morris,EvanD
• 通讯作者: Morris,EvanD