Affinity and selectivity of [ ¹¹C]-(+)-PHNO for the D3 and D2 receptors in the rhesus monkey brain in vivo

Although [ ¹¹C]-(+)-PHNO has enabled quantification of the dopamine-D3 receptor (D3R) in the human brain in vivo, its selectivity for the D3R is not sufficiently high to allow us to disregard its binding to the dopamine-D2 receptor (D2R). We quantified the affinity of [ ¹¹C]-(+)-PHNO for the D2R and D3R in the living primate brain. Two rhesus monkeys were examined on four occasions each, with [ ¹¹C]-(+)-PHNO administered in a bolus + infusion paradigm. Varying doses of unlabeled (+)-PHNO were coadministered on each occasion (total doses ranging from 0.09 to 5.61 μg kg ^-1). The regional binding potential (BP _ND) and the corresponding doses of injected (+)-PHNO were used as inputs in a model that quantified the affinity of (+)-PHNO for the D2R and D3R, as well as the regional fractions of the [ ¹¹C]-(+)-PHNO signal attributable to D3R binding. (+)-PHNO in vivo affinity for the D3R (K _d/f _ND ∼ 0.23-0.56 nM) was 25- to 48-fold higher than that for the D2R (K _d/f _ND ∼ 11-14 nM). The tracer limits for (+)-PHNO (dose associated with D3R occupancy ∼ 10%) were estimated at ∼0.02-0.04 μg kg ^-1 injected mass for anesthetized primate and at 0.01-0.02 μg kg ^-1 for awake human positron emission tomography (PET) studies. Our data enabled a rational design and interpretation of future PET studies with [ ¹¹C]-(+)-PHNO.