Characterization of a New Metabotropic Glutamate Receptor Subtype 5 PET Ligand

新型代谢型谷氨酸受体亚型 5 PET 配体的表征

• 批准号: 8261691
• 负责人: Christine Delorenzo
• 金额: $ 17.13万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-09-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8261691
• 关键词: Address; Affect; Affinity; Anxiety; Anxiety Disorders; Arterial Lines; Binding; Biomedical Engineering; Brain; Clinical; Clinical assessments; Cluster Analysis; Consent Forms; Data; Databases; Depressed mood; Detection; Development; Diagnosis; Diagnostic; Disease; Early treatment; Enrollment; Ensure; Exhibits; Fragile X Syndrome; Functional disorder; Glutamates; Goals; Grant; Human; Human Volunteers; Image; Image Analysis; Imagery; In Vitro; Individual; Institutional Review Boards; Ketamine; Kinetics; Knowledge; Learning; Life; Ligand Binding; Ligands; Major Depressive Disorder; Measurement; Measures; Medical Imaging; Mental Depression; Mental disorders; Mentors; Metabotropic Glutamate Receptors; Methods; Modality; Modeling; Monitor; Mood Disorders; Neurobiology; Neurotransmitters; Outcome; Outcome Measure; Oximes; Parkinson Disease; Patients; Performance; Pharmaceutical Preparations; Plasma; Positron-Emission Tomography; Pre-Clinical Model; Preparation; Procedures; Protocols documentation; Public Health; Radiochemistry; Recruitment Activity; Reporting; Research; Research Personnel; Risk; Sampling; Scanning; Schizophrenia; Sensory Receptors; Series; Specificity; Structure; System; Techniques; Testing; Therapeutic; Time; Tissues; Tracer; Treatment Effectiveness; Variant; Venous; Writing; addiction; base; cost; density; experience; image processing; imaging modality; improved; in vivo; insight; meetings; nervous system disorder; novel; patient population; public health relevance; radioligand; receptor; response; technique development; treatment response

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.

描述（由申请人提供）：拟议的研究涉及表征新型正电子发射断层扫描（PET）放射配体，3-（6-甲基吡啶-2-乙炔基）-环己基-2-烯酮-o -11C-甲基肟（[11C]ABP688），人类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mGluR5参与抑郁症的病理生理。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。随着对mGluR5的关注越来越多，建立这种受体的可靠成像方法变得越来越重要。PET提供了活体人脑神经受体系统的可视化，使PET成为量化体内mGluR5的理想方式。为此，[11C]ABP688是一种体外高选择性的mGluR5变构拮抗剂，在体内对mGluR5具有高选择性，最近被开发用于人体。通过[11C]ABP688定量mGluR5变异可以有很多用途，从抑郁症或其他疾病的可能指标，到对个体治疗效果的潜在监测，再到在治疗前提供关于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必须在人体中进行适当的表征，以提供准确的靶标定量。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。通过拟议的研究，与我的导师（精神病人群体PET研究领域的领导者）的结构化会议，以及课程作业和与项目贡献者的定期会议，我将扩展我在神经生物学，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。在此过程中，我不仅将增强对[11C]ABP688和mGluR5的现有知识，而且还将学习一套开发和使用PET示踪剂的程序，我可以作为独立研究者使用。具体而言，我计划：(1)确定[11C]ABP688的最佳建模技术和扫描时间，以确保可靠准确的量化。利用这些最优方法建立个体间的结合变异。(2)研究在没有动脉线的情况下计算全血浆输入函数的方法，提高受试者舒适度，降低扫描成本。使用数学方法，可以从静脉样本或sinogram数据对动脉输入进行建模。消除对动脉导管的需要可能会减少目前在解决公共卫生问题中广泛使用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)比较抑郁组和对照组mGluR5的分布和密度。这将为mGluR5功能障碍在抑郁症中的作用机制提供新的见解。这些研究的目标是增加对mGluR5的了解，并开发出急需的可靠的mGluR5 PET成像方法。