Characterization of in vivo pharmacokinetic properties of the dopamine D1 receptor agonist DAR-0100A in nonhuman primates using PET with [C-11] NNC112 and [C-11] raclopride

DAR-0100A, the active enantiomer of dihydrexidine, is a potent dopamine D1 agonist under investigation for treatment of cognitive impairment and negative symptoms of schizophrenia. We measured the dose-occupancy relationship for DAR-0100A at D1 receptors using positron emission tomography (PET) imaging in baboons with [C-11] NNC112 and its binding to D2 with [C-11] raclopride. Two baboons were scanned with [C-11] NNC112 at baseline and after three different doses of DAR-0100A. Two baboons were scanned with [C-11] raclopride at baseline and after one dose of DAR-0100A. Occupancy (Delta BPND) was computed in the striatum and cortex. A clear relationship was observed between plasma concentration of DAR-0100A and Delta BPND. Delta BPND was larger in the striatum than in the cortex, consistent with reports showing that 25% of [C-11] NNC112 BPND in the cortex is attributed to 5-HT2A. Plasma EC50 estimates ranged from 150 to 550 ng/mL according to the constraints on the model. There was no detectable effect of DAR-0100A on [C-11] raclopride BPND. These data suggest that at doses likely to be administered to patients, occupancy will not be detectable with [C-11] NNC112 PET and binding of DAR-0100A to D2 will be negligible. This is the first demonstration with PET of a significant occupancy by a full D1 agonist in vivo. Journal of Cerebral Blood Flow & Metabolism (2011) 31, 293-304; doi:10.1038/jcbfm.2010.91; published online 23 June 2010