Purpose: The in vitro and in vivo evaluation of the selective, high affinity (human CB1 IC(50) 0.49 nM) inverse agonist CB1R tracer [(11)C]CB-119, a close analog of the previously disclosed [(18)F]MK-9470, was undertaken.
Procedures: [(11)C]CB-119 was synthesized with high specific activity by alkylation of a phenolic precursor with [(11)C]methyl iodide. In vitro autoradiographic studies using rhesus brain slices were carried out using [(3)H]CB-119, and in vivo imaging studies were carried out using [(11)C]CB-119 in rhesus monkeys under baseline and blocked conditions.
Results: Autoradiographic studies in rhesus brain showed the expected distribution pattern for CB1R with highest binding in the cerebral cortex, cerebellum, caudate/putamen, globus pallidus, substantia nigra, and hippocampus. Lower binding was seen in the posterior hypothalamus, ventral tegmental area, and periventricular gray area, and the lowest binding was in the thalamic nuclei. The binding of [(3)H]CB-119 was fully blocked by the addition of 10 microM CB-119. Rhesus positron emission tomography imaging studies showed very good brain uptake and a distribution pattern consistent with that seen in the autoradiographic studies. The kinetics of tracer uptake was slow. The brain uptake was blocked by pretreatment with taranabant, a CB1R inverse agonist. The specific signal (total/nonspecific) in rhesus putamen at 90 min was approximately 6:1.
Conclusions: [(11)C]CB-119 is a suitable tracer for imaging central CB1 receptors.