Effect of risperidone on high-affinity state of dopamine D₂ receptors: A PET study with agonist ligand [¹¹C](R)-2-CH ₃O-N-npropylnorapomorphine

The increased proportion of the high-affinity state of dopamine D _2/3receptors (D_2,high) is assumed to correlate with dopamine hypersensitivity, implying a relationship with psychotic symptoms observed in psychiatric disorders such as schizophrenia. [¹¹C](R)-2- CH₃O-N-n-propylnorapomorphine ([¹¹C]MNPA), which has an agonistic property to dopamine D₂ receptors (D₂Rs), is expected to bind preferentially to D_2,high. The occupancy of dopamine D₂Rs by antagonists to receptors has not been investigated using [¹¹C]MNPA. We compared dopamine D₂R occupancies by risperidone, an antagonist to receptors, between [¹¹C]MNPA and [ ¹¹C]raclopride to confirm whether risperidone occupies D _2,high andD_2,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 [¹¹C]MNPA and [¹¹C]raclopride were 22-65% and 24-69%, respectively. In the striatum, ED₅₀ values measured with [ ¹¹C]MNPA and [¹¹C]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,high and D _2,low at almost identical proportions in a dose-dependent manner