Characterization of a New Metabotropic Glutamate Receptor Subtype 5 PET Ligand

描述(由申请人提供)：拟议的研究涉及在人类中表征新型正电子发射断层扫描放射性配体3-(6-Methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-11C-methyl-oxime([11C]ABP688)，它是一种代谢性谷氨酸受体亚型5(MGluR5)的拮抗剂。大量不同的证据表明mGluR5与抑郁症的病理生理学有关。此外，mGluR5功能障碍与焦虑、精神分裂症、成瘾、帕金森病和脆性X综合征等疾病有关。随着人们对mGluR5的关注越来越多，建立可靠的方法对这种受体进行成像变得越来越重要。PET提供了活体人脑神经感受器系统的可视化，使PET成为体内定量mGluR5的理想方法。为此，[11C]ABP688是一种在体外对mGluR5具有高选择性的变构拮抗剂，在体内对mGluR5具有高选择性，最近被开发用于人类。[11C]ABP688对mGluR5变异的量化可用于多种目的，从抑郁症或其他疾病的可能指示器，到个体治疗效果的潜在监测，再到在治疗前提供有关潜在治疗结果的个性化信息。然而，与任何新开发的PET示踪剂一样，[11C]ABP688必须在人体内得到适当的表征，以便提供其靶标的准确定量。因此，我将定义并执行一个协议来表征[11C]ABP688，它可以推广到任何新的PET配体。通过提议的研究，与我的导师(精神病患者群体PET研究领域的领导者)的有组织的会议，以及课程作业和与项目贡献者的定期会议，我将扩大我在神经生物学、放射化学、PET成像和分析、临床评估和情感障碍方面的专业知识。通过这样做，我不仅将增强当前对[11C]ABP688和mGluR5的了解，还将学习一套开发和使用PET示踪剂的程序，我可以作为一名独立研究员聘用这些程序。具体来说，我计划：(1)确定[11C]ABP688的最佳建模技术和扫描时间，以确保可靠和准确的定量。将使用这些最佳方法建立个体内结合变异。(2)研究在不需要动脉导管的情况下计算全血浆输入功能的方法，提高受试者的舒适度，降低扫描成本。使用数学方法，可以根据静脉样本或正弦波图数据对动脉输入进行建模。消除对动脉管道的需求可能会减少目前在解决公共卫生问题方面广泛使用PET的障碍。(3)研究[11C]ABP688对内源性谷氨酸的敏感性，以确定该配体是否可用于监测神经和精神疾病中谷氨酸水平的变化。(4)比较抑郁症组和对照组mGluR5的分布和密度。这将为深入了解抑郁症中mGluR5功能障碍的机制提供依据。这些研究的目标是增加对mGluR5的了解，并开发急需的可靠的mGluR5 PET成像方法。 公共卫生相关性：这项提案中概述的研究将用于开发一种可靠的方法，对抑郁症患者大脑中可能发生变化的受体进行成像。这种受体的准确测量可用作抑郁症的诊断指标，以便及早干预，或有助于预测或监测治疗反应。这将允许对抑郁症和相关疾病的个性化治疗。

DESCRIPTION (provided by applicant): The proposed research involves characterizing the novel Positron Emission Tomography (PET) radioligand, 3- (6-Methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-11C-methyl-oxime ([11C]ABP688), an antagonist of the metabotropic glutamate receptor subtype 5 (mGluR5), in humans. A large body of diverse evidence implicates mGluR5 in the pathophysiology of depression. In addition, mGluR5 dysfunction has been associated with disorders such as anxiety, schizophrenia, addiction, Parkinson's disease, and fragile X syndrome. As focus intensifies on mGluR5, it is becoming increasingly important to establish reliable methods of imaging this receptor. PET provides visualization of neuroreceptor systems in living human brain, making PET an ideal modality to quantify mGluR5 in vivo. To this end, [11C]ABP688, a highly selective allosteric antagonist of the mGluR5 in vitro with high selectivity for mGluR5 in vivo, has recently been developed for use in humans. Quantification of mGluR5 variation by [11C]ABP688 could serve many purposes, from a possible indicator of depression or other disorders, to a potential monitor of treatment effectiveness in an individual, to providing personalized information prior to treatment about potential therapeutic outcomes. However, as with any newly developed PET tracer, [11C]ABP688 must be properly characterized in humans in order to provide accurate quantification of its target. Therefore, I will define and perform a protocol to characterize [11C]ABP688, which can be generalized to any novel PET ligand. Through the proposed study, structured meetings with my mentors (leaders in the field of PET research of psychiatric patient populations), as well as coursework and regular meetings with project contributors, I will expand my expertise in neurobiology, radiochemistry, PET imaging and analysis, clinical assessment, and affective disorders. In doing so, I will not only enhance the current knowledge of [11C]ABP688 and mGluR5, but also learn a set procedures for developing and using PET tracers that I can employ as an independent investigator. Specifically, I plan to: (1) Determine the optimal modeling techniques and scanning time for [11C]ABP688, to ensure reliable and accurate quantification. Intra- individual binding variation will be established using these optimal methods. (2) Examine methods to calculate a full plasma input function without an arterial line, improving subject comfort and decreasing scan cost. Using mathematical approaches, it may be possible to model arterial input from either venous samples or sinogram data. Eliminating the need for arterial lines may reduce current barriers to widespread PET use in addressing public health issues. (3) Investigate sensitivity of [11C]ABP688 to endogenous glutamate to determine if this ligand can be used to monitor glutamate level variations in neurologic and psychiatric disorders. (4) Compare mGluR5 distribution and density in depressed and control subjects. This will provide insight into the mechanism of mGluR5 dysfunction in depression. The goal of these studies is an increased knowledge of mGluR5 and the development of much needed reliable mGluR5 PET imaging methods. PUBLIC HEALTH RELEVANCE: The studies outlined in this proposal will be used to develop a reliable method of imaging a receptor in the brain that may be altered in depressed patients. Accurate measurements of this receptor may be used as a diagnostic indicator of depression, allowing earlier interventions, or may help predict or monitor treatment response. This would allow personalization of treatment for depression and related disorders.