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

描述(申请人提供)：kappa阿片受体(Kors)与许多神经精神障碍有关，包括抑郁、焦虑和与压力相关的障碍、成瘾以及阿尔茨海默病。经过验证的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，还没有用于人体成像KOR的PET放射性示踪剂，尽管已经有了其他阿片受体的示踪剂。我们首次在人体内进行了一对选择性KOR激动剂([11C]GR103545)和拮抗剂([11C]LY2795050)示踪剂的初步测试，用于体内KOR的定量。这一点很重要，因为拮抗剂示踪剂测量受体的总可用性，而激动剂示踪剂仅测量配置在高亲和力状态的受体的可用性，高亲和力状态是功能状态或活性状态。因此，一对激动剂/拮抗剂对PET示踪剂的可用性将首次允许同时评估KOR受体的总表达，以及更重要的是，配置在其功能状态的KOR部分，这可能会在疾病条件下发生变化。基于我们最初的人类经验，这项建议的第一个主要目标是建立[11C]GR103545和[11C]LY2795050作为PET显像剂的可靠性和有效性，用于量化人体内的KOR。选择性PET显像剂的验证和成功应用将对阿片系统和KOR的研究和阐明、对该受体亚型参与脑疾病的进一步了解以及对广泛病理条件的新疗法的开发具有广泛的影响。许多精神障碍，主要是抑郁、焦虑和成瘾，在患病率、病程和/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提供对这些疾病的生化过程的洞察，并为针对性别的药物疗法的治疗开发提供信息。在这项研究中，PET成像是一个强大的工具，因为它允许研究活体受试者中受体的可用性。因此，这项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和处于功能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体的区域密度随着年龄的增长而减少，我们还将探索是否存在年龄对KOR的影响。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类型的受体截然不同。这项提案中的调查将有助于为这个问题提供答案。

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.