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

Abstract

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. [(11)C]-(+)-PHNO is a PET D(2) agonist radioligand and therefore provides a preferential measure of the D(2) (high) receptors. In contrast, [(11)C]raclopride is an antagonist radioligand and thus binds with equal affinity to the D(2) high- and low-affinity states. The aim was to compare the brain uptake, distribution and binding characteristics between [(11)C]-(+)-PHNO and [(11)C]raclopride in volunteers using a within-subject design. Both radioligands accumulated in brain areas rich in D(2)/D(3)-receptors. However, [(11)C]-(+)-PHNO showed preferential uptake in the ventral striatum and globus pallidus, while [(11)C]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 [(11)C]raclopride, equal in the ventral-striatum (3.4 vs. 3.3), and higher in the globus pallidus for [(11)C]-(+)-PHNO (1.8 vs. 3.3). Moreover [(11)C]-(+)-PHNO kinetics in the globus pallidus showed a slower washout than other regions. One explanation for the preferential binding of [(11)C]-(+)-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 [(11)C]-(+)-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.

Figure 1

Brain distribution of [¹¹C]‐(+)‐PHNO and [¹¹C]raclopride shown as mean standard uptake value (SUV) images. Arrows indicate, in axial views, the substantia nigra (1), globus pallidus (2) and ventral striatum (3). The lower threshold for the images corresponds to the mean SUV activity in the cerebellum. The sagittal view indicates the levels of the axial (1 and 2) and coronal (3) projections. The images correspond to the average of the twelve healthy controls.

Figure 2

Binding concentration distribution maps showing the percentage of striatal uptake distribution with [¹¹C]‐(+)‐PHNO and [¹¹C]raclopride. The percentage images correspond to axial projections rendered over a T1 template in the MNI space. The images correspond to the average of the twelve healthy controls. Z, corresponds to the millimeters above (+) or below (−) the anterior commissure in the AC‐PC plane.

Figure 3

Time activity curves (TAC) showing [¹¹C]‐(+)‐PHNO (a) and [¹¹C]raclopride (b) binding kinetics in the caudate, putamen, ventral striatum, globus pallidus, cerebellum and substantia nigra (only in [¹¹C]‐(+)‐PHNO). The TACs correspond to the average of the twelve healthy controls. Y axes represent standard uptake values.

Figure 4

Binding Potential (BP) for [¹¹C]‐(+)‐PHNO and [¹¹C]raclopride in each ROI. The BPs correspond to the mean of twelve healthy controls. Error bars represent standard deviation. Significant differences are presented between radiotracers (F _[9,110] = 29.5, P < 0.001) per ROI. (* P < 0.01, Bonferroni corrected). SRTM, Simplified reference tissue model.