11C-JHU75528: a radiotracer for PET imaging of CB1 cannabinoid receptors.

UNLABELLED The development of the radioligands for PET imaging of the cerebral cannabinoid receptor (CB1) is of great importance for studying its role in neuropsychiatric disorders, obesity, and drug dependence. None of the currently available radioligands for CB1 are suitable for quantitative PET, primarily because of their insufficient binding potential (BP) in brain or low penetration through the blood-brain barrier (BBB). The goal of this study was to evaluate 11C-JHU75528, an analog of the selective CB1 antagonist rimonabant, in vivo as a potential CB1 radioligand for PET. METHODS The brain regional distribution and pharmacology of 11C-JHU75528 have been evaluated in vivo in mice (dissection) and baboons (PET). RESULTS 11C-JHU75528 readily entered the mouse and baboon brain and specifically and selectively labeled cerebral CB1 receptors. The ratio of striatum to brain stem in mice and the binding potential (BP) in the baboon putamen were 3.4 and 1.3-1.5, respectively. The specific binding of 11C-JHU75528 in vivo was blocked by preinjection of nonlabeled JHU75528. Administration of rimonabant (1 mg/kg, intravenously) also blocked the specific binding of 11C-JHU75528 in the mouse and baboon brain, whereas various central noncannabinoid drugs did not significantly reduce the 11C-JHU75528 binding in the mouse brain. 11C-JHU75528 formed several hydrophilic metabolites, but only a minute fraction of metabolic radioactivity penetrated the BBB. CONCLUSION 11C-JHU75528 holds promise as a radiotracer with suitable imaging properties for quantification of CB1 receptors in the human brain.