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.
