In Vivo Binding of Antipsychotics to D3 and D2 Receptors: A PET Study in Baboons with [11C]-(+)-PHNO

Measuring the in vivo occupancy of antipsychotic drugs at dopamine D₂ and D₃ receptors separately has been difficult because of the lack of selective radiotracers. The recently developed ¹¹C]-(+)-PHNO is D₃-preferring, allowing estimates of the relative D₂ and D₃ binding of antipsychotic drugs. We used positron emission tomography (PET) imaging in baboons with ¹¹C]-(+)-PHNO to examine the binding of clozapine and haloperidol to D₂ and D₃ receptors. Four animals were scanned with dynamically acquired PET and arterial plasma input functions. Test and retest scans were acquired in single scanning sessions for three subjects to assess the reproducibility of ¹¹C]-(+)-PHNO scans. Four additional scans were acquired in each of three subjects following single doses of antipsychotic drugs (clozapine 0.5534 mg/kg, haloperidol 0.0109 mg/kg, two administrations per drug per subject) and compared with baseline scans. The percent change in binding (ΔBP_ND) following challenges with antipsychotic drugs was measured. A regression model, based on published values of regional D₂ and D₃ fractions of ¹¹C]-(+)-PHNO BP_ND in six brain regions, was used to infer occupancy at D₂ and D₃ receptors. BP_ND following antipsychotic challenge decreased in all regions. Estimated D₂ : D₃ selectivity was 2.38 for haloperidol and 5.25 for clozapine, similar to published in vitro values for haloperidol (3.03), but slightly higher for clozapine (2.82). These data suggest that acute doses of clozapine and haloperidol bind to D₃ receptors in vivo, and that the lack of D₃ occupancy by antipsychotics observed in some recent imaging studies may be because of other phenomena.