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，以非侵入性地监测从大鼠到非人灵长类动物的活体受试者中CB 1受体的体内表达。已经确定，通过CB 1受体起作用的内源性和外源性大麻素涉及多种行为和神经功能的控制。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这样的假设，即异常CB！受体功能可能导致多种疾病的发病机制，例如呕吐、炎症、青光眼、疼痛、惊厥、肥胖、酒精中毒、中风和神经变性疾病，包括MS、HD、AD和PD。开发高比活度、放射性标记、选择性CB！PET的受体拮抗剂将使得在体内重复地定量与CB/1受体的结合成为可能，这将打开脑成像以及基础研究中的许多临床领域，以研究CB参与的病理生理学。受体在神经精神和神经退行性疾病中的作用。这样的PET探针必须具有优异的亲和力和受体选择性以及穿过BBB的快速渗透性。我们选择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-甲酰胺（NES 0327，Ki = 340 fM）和SR 141716 A（Ki = 1 nM）作为我们开发CBI受体PET探针的潜在先导。所开发的探针将应用于研究CB 1通路的参与，并允许在各种病症中对CB 1受体进行可视化和定量，所述病症例如自杀行为、酒精中毒、抑郁、炎症、青光眼、癫痫、肥胖和神经变性疾病，其中报道了CB 1受体水平的上调或下调。此外，受体的PET成像探针将为开发基于CB/1药理学的治疗剂提供有用的帮助。

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.