Effect of risperidone on high-affinity state of dopamine D2 receptors: a PET study with agonist ligand [11C](R)-2-CH3O-N-n-propylnorapomorphine

The increased proportion of the high-affinity state of dopamine D-2/3 receptors (D-2,D-high) is assumed to correlate with dopamine hypersensitivity, implying a relationship with psychotic symptoms observed in psychiatric disorders such as schizophrenia. [C-11](R)-2-CH3O-N-n-propylnorapomorphine ([C-11]MNPA), which has an agonistic property to dopamine D-2 receptors (D(2)Rs), is expected to bind preferentially to D-2,D-high. The occupancy of dopamine D(2)Rs by antagonists to receptors has not been investigated using [C-11]MNPA. We compared dopamine D2R occupancies by risperidone, an antagonist to receptors, between [C-11]MNPA and [C-11]raclopride to confirm whether risperidone occupies D-2,D-high and D-2,D-low at almost identical proportions. PET studies were performed on 11 healthy men under resting condition and following oral administration of a single dose of risperidone (0.5-2.0 mg). Striatal receptor occupancy for each radioligand was calculated. The relationship between dose or plasma concentration of risperidone and dopamine D2R occupancy was calculated. Striatal dopamine D2R occupancies measured with [C-11]MNPA and [C-11]raclopride were 22-65% and 24-69%, respectively. In the striatum, ED50 values measured with [C-11]MNPA and [C-11]raclopride were 0.98 and 1.03 mg, respectively. The striatal ED50 values as calculated from plasma concentration were 9.15 ng/ml and 8.01 ng/ml, respectively. Almost identical occupancies and ED50 values were observed between the two radioligands, indicating that risperidone bound to D-2,D-high and D-2,D-low at almost identical proportions in a dose-dependent manner.