11C NMSP receptor occupancy by clozapine and haloperidol in schizophrenic subjects

The receptor binding profile of clozapine is remarkable. The drug has a relatively low but measurable affinity at the D2 postsynaptic receptor, lower by more than an order of magnitude than any other marketed antipsychotic. It also has almost equivalent affinity to S2, D1, A1, A2, and muscarinic receptors. Moreover, recent work demonstrates a high affinity for the D4 receptor as well. In prior work our group has shown that mean percent of 11C NMSP receptor occupancy in the striatum with haloperidol treatment was 80% in comparison with clozapine at 19%. In this presentation we analyzed the occupancy of NMSP receptors by clozapine vs. haloperidol in extra-striatal areas. Six schizophrenic subjects were entered into the study, all signed informed consent. They had 11C-NMSP PET scans done after consecutive two-week drug free, six-week haloperidol 30 mg/day and six-week 450 mg/day clozapine trials. Eight regions of interest were analyzed for differential binding using a twelve-minute epoch 40 to 52 minutes after spiperone injection. This time period was chosen to optimize the scans for detection of dopamine receptor binding. Clozapine showed 100% displacement of spiperone throughout the cortex compared to 2% to 17% displacement by haloneridol. Thalamic displacement was equivalent for the two drugs.