Brain region binding of the D2/3 agonist [11C]-(+)-PHNO and the D2/3 antagonist [11C]raclopride in healthy humans

The D-2 receptors exist in either the high- or low-affinity state with respect to agonists, and while agonists bind preferentially to the high-affinity state, antagonists do not distinguish between the two states. high [C-11]-(+)-PHNO is a PET D-2 agonist radioligand and therefore provides a preferential measure of the D2 receptors. In contrast, [C-11]raclopride is an antagonist radioligand and thus binds with equal affinity to the D2 high- and low-affinity states. The aim was to compare the brain uptake, distribution and binding characteristics between [C-11]-(+)-PHNO and [C-11]raclopride in volunteers using a within-subject design. Both radioligands accumulated in brain areas rich in D-2/D-3-receptors. However, [C-11]-(+)-PHNO showed preferential uptake in the ventral striatum and globus pallidus, while [C-11]raclopride showed preferential uptake in the dorsal striatum. Mean binding potentials were higher in the putamen (4.3 vs. 2.8) and caudate (3.4 vs 2.1) for [C-11]raclopride, equal in the ventral-striatum (3.4 vs. 3.3), and higher in the globus pallidus for [C-11]-(+)PHNO (1.8 vs. 3.3). Moreover [C-11]-(+)-PHNO kinetics in the globus pallidus showed a slower washout than other regions. One explanation for the preferential binding of [C-11]-(+)-PHNO in the globus pallidus and ventral-striatum could be the presence of a greater proportion of high- vs. low-affinity receptors in these areas. Alternatively, the observed distribution could also be explained by a preferential binding of D-3-over-D-2 with [C-11]-(+)-PHNO. This differential binding of agonist vs. antagonist radioligand, especially in the critically important region of the limbic striatum/pallidum, offers new avenues to investigate the role of the dopamine system in health and disease.