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

描述（由申请人提供）：κ阿片样物质受体（KOR）与许多神经精神疾病有关，包括抑郁症、焦虑和应激相关疾病、成瘾以及阿尔茨海默病。 有效的PET显像剂的可用性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，还没有PET放射性示踪剂用于人类对KOR进行成像，尽管其他阿片受体的示踪剂已经可用。 我们是第一个在人体中对一对选择性KOR激动剂（[11 C] GR 103545）和拮抗剂（[11 C] LY 2795050）示踪剂进行初步测试，用于体内定量KOR。 这是重要的，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在高亲和力状态（其为功能或活性状态）的受体的可用性。 因此，PET示踪剂的激动剂/拮抗剂对的可用性将首次允许同时评估总KOR受体表达，并且同样重要的是，在其功能状态中配置的KOR部分，其可能在疾病状况中变化。 基于我们最初的人类经验，本提案的第一个主要目标是确定[11 C] GR 103545和[11 C] LY 2795050作为PET显像剂用于人体KOR定量的可靠性和有效性。 验证和成功应用的选择性PET显像剂的KOR将有广泛的影响，在调查和阐明阿片类药物系统和KORs，在获得进一步了解这种受体亚型参与大脑疾病，并在开发新的治疗方法的广泛的病理条件。 许多精神疾病，主要是抑郁症、焦虑症和成瘾症，在患病率、时间进程和/或治疗反应方面显示出很大的性别差异。 了解神经受体表达和功能的性别差异，将提供深入了解这些疾病的生化过程，并告知性别特异性药物治疗的治疗发展。 PET成像是这项研究的有力工具，因为它允许研究活体人类受试者中的受体可用性。 因此，本申请的第二个主要目标是使用经验证的KOR选择性PET示踪剂来研究性别和年龄对活脑中总受体以及功能性高亲和力状态中配置的部分的可用性的影响。 我们还将探讨是否有年龄对KOR的影响，因为大多数受体和转运蛋白的区域密度随着年龄的增长而下降。 然而，值得注意的是，5阿片受体密度显示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的调节明显不同。 本文的研究将有助于回答这一问题。 公共卫生相关性：该授权申请旨在验证κ阿片受体放射性示踪剂碳-11 GR 103545和碳-11 LY 2795050作为正电子发射断层扫描（PET）成像生物标志物用于生物医学成像研究。 κ阿片受体被认为与许多精神障碍、成瘾行为和其他脑部疾病有关，因此，经验证的PET成像生物标志物的可用性将为生物医学研究界提供一种非侵入性的方式来研究κ阿片受体蛋白在正常条件下的功能和调节，以及其在疾病中可能的功能障碍。 此外，PET成像生物标志物可用于研究药物是否达到其预期目标并产生治疗效果，并确定最合适的剂量，副作用最小，因此有助于开发新的有效治疗各种精神疾病，成瘾和其他脑部疾病的方法。

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. PUBLIC HEALTH RELEVANCE: This grant application proposes to validate the kappa opiate receptor radiotracers carbon-11 GR103545 and carbon-11 LY2795050 as a positron emission tomography (PET) imaging biomarkers for use in biomedical imaging research. The kappa opiate receptor is believed to be involved in a number of psychiatric disorders, addictive behaviors, and other diseases of the brain, therefore the availability of validated PET imaging biomarkers will provide the biomedical research community with a non-invasive way of investigating the function and regulation of the kappa opiate receptor protein under normal conditions, as well as its possible dysfunction in diseases. Furthermore, PET imaging biomarkers can be used to investigate whether a drug reaches its intended target and produces therapeutic efficacy, and determine the most appropriate doses with minimal side effects, therefore aiding in the development of new and effective treatments for various psychiatric disorders, addictions, and other diseases of the brain.