Development of PET Probes for Quantifying CB1 Receptor Binding

描述（由申请人提供）：本提案的总体目标是开发PET成像探针，以无创监测从大鼠到非人灵长类动物活体中CB^受体的体内表达。已经确定内源性和外源性大麻素通过CBi受体参与控制多种行为和神经功能。大麻素激动剂和拮抗剂的广泛临床前和临床研究已经产生了异常的CB！受体功能可能有助于多种疾病的发病机制，如呕吐、炎症、青光眼、疼痛、抽搐、肥胖、酗酒、中风和神经退行性疾病，包括MS、HD、AD和PD。开发高比活性、放射性标记、选择性CB！PET受体拮抗剂将使体内与CB/1受体的定量结合成为可能，这将在脑成像和基础研究中开辟许多临床领域，以研究CB累及的病理生理！神经精神和神经退行性疾病中的受体。这样的PET探针必须具有优异的亲和力和受体选择性以及快速通过血脑屏障的渗透性。我们选择了n -哌啶基-[8-氯-1-（2,4-二氯苯基）-1,4,5,6-四氢苯并[6,7]环庚-[1,2-c]吡唑-3-碳酰胺（NESS 0327, Ki = 340 fM）和SR141716A （Ki = 1nM）作为CBI受体PET探针开发的潜在先导物。所开发的探针将应用于研究CB^通路的参与，并允许可视化和量化各种情况下的CBi受体，如自杀行为、酗酒、抑郁、炎症、青光眼、癫痫、肥胖和神经退行性疾病，其中CBi受体水平的上调或下调被报道。此外，PET受体成像探针将为开发基于CB/1药理学的治疗药物提供有益的帮助。

DESCRIPTION (provided by applicant): The overall objective of this proposal is to develop PET imaging probes to non-invasively monitor in vivo expression of CB^ receptors in living subjects from rats to non-human primates. It has been established that endogenous and exogenous cannabinoids acting through the CBi receptor are implicated in the control of a variety of behavioral and neurological functions. Extensive preclinical as well as clinical studies of cannabinoid agonists and antagonists have generated the hypotheses that abnormal CB! receptor function may contribute to the pathogenesis of a diverse range of diseases such as emetic, inflammatory, glaucoma, pain, convulsive, obesity, alcoholism, stroke and neurodegenerative diseases including MS, HD, AD and PD. Development of high specific activity, radiolabeled, selective CB! receptor antagonists for PET would make it possible to quantify binding to CB/1 receptors in vivo, repeatedly, which would open many clinical areas in brain imaging as well as in basic research to study the pathophysiology of the involvement of CB! receptors in neuropsychiatric and neurodegenerative diseases. Such a PET probe must have excellent affinity and receptor selectivity and rapid permeability across BBB. We have chosen N-piperidinyl-[8-chloro-1- (2,4-dichlorophenyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta-[1,2-c]pyrazole-3-carbo-xamide (NESS 0327, Ki = 340 fM) and SR141716A (Ki = 1nM) as our potential lead for PET probe development for CBI receptor. The developed probes will have application in the study of involvement of CB^ pathways and permit visualization and quantification of CBi receptors in various conditions such as suicidal behavior, alcoholism, depression, inflammatory, glaucoma, epilepsy, obesity and neurodegenerative diseases in which up or down regulation of CBi receptor levels are reported. Furthermore, the PET imaging probes for receptors will provide useful aid to develop therapeutic agents based on CB/1 pharmacology.