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 mu g kg-1). The regional binding potential (BPND) 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 (Kd/fND similar to 0.230.56 nM) was 25- to 48-fold higher than that for the D2R (Kd/fND similar to 1114 nM). The tracer limits for (+)-PHNO (dose associated with D3R occupancy similar to 10%) were estimated at similar to 0.020.04 mu g kg-1 injected mass for anesthetized primate and at 0.010.02 mu g 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. Synapse, 2012. (C) 2011 Wiley Periodicals, Inc.