In vivo binding of antipsychotics to D3 and D2 receptors

Measuring the in vivo occupancy of antipsychotic drugs at dopamine D-2 and D-3 receptors separately has been difficult because of the lack of selective radiotracers. The recently developed [C-11]-(+)-PHNO is D-3-preferring, allowing estimates of the relative D-2 and D-3 binding of antipsychotic drugs. We used positron emission tomography (PET) imaging in baboons with [C-11]-(+)-PHNO to examine the binding of clozapine and haloperidol to D-2 and D-3 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 [C-11]-(+)-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 (Delta BPND) following challenges with antipsychotic drugs was measured. A regression model, based on published values of regional D-2 and D-3 fractions of [C-11]-(+)-PHNO BPND in six brain regions, was used to infer occupancy at D-2 and D-3 receptors. BPND following antipsychotic challenge decreased in all regions. Estimated D-2 : D-3 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 D-3 receptors in vivo, and that the lack of D-3 occupancy by antipsychotics observed in some recent imaging studies may be because of other phenomena. Neuropsychopharmacology (2011) 36, 887-895; doi:10.1038/npp.2010.228; published online 22 December 2010