Characterization of in vivo pharmacokinetic properties of the dopamine D1 receptor agonist DAR-0100A in nonhuman primates using PET with [¹¹C] NNC112 and [¹¹C] 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 [¹¹C] NNC112 and its binding to D2 with [¹¹C] raclopride. Two baboons were scanned with [¹¹C] NNC112 at baseline and after three different doses of DAR-0100A. Two baboons were scanned with [¹¹C] raclopride at baseline and after one dose of DAR-0100A. Occupancy (ΔBP ND) was computed in the striatum and cortex. A clear relationship was observed between plasma concentration of DAR-0100A and ΔBP ND. ΔBP ND was larger in the striatum than in the cortex, consistent with reports showing that 25% of [¹¹C] NNC112 BP ND in the cortex is attributed to 5-HT 2A. 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 [¹¹C] raclopride BP ND. These data suggest that at doses likely to be administered to patients, occupancy will not be detectable with [¹¹C] 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.