The antipsychotic effects of typical neuroleptics are mediated by blockade of dopamine D2 type receptors. It has been proposed that the antipsychotic effects of these drugs are mediated by blockade of cortical and limbic dopamine D2 receptors while extrapyramidal site effects are mediated by dorsolateral striatal D2 receptor blockade. To date, most PET and SPECT studies of antipsychotic drug blockade of D2 receptors have examined the striatum. There are a number of studies which suggest that the atypical profile of clozapine is mediated at least in part by selective effects on cortical and limbic dopaminergic neurotransmission. Our group has developed [18F] N-allyl-5-fluoropropylepidepride as a PET radioligand for visualization of extrastriatal D2 receptors in man. Our Phase I and early Phase II IND studies demonstrate that this ligand allows excellent visualization and quantitation of extrastriatal D2 receptors in man. Wed propose to use [18F] N-allyl-5-fluoropropylepidepride PET studies to evaluate 15 schizophrenic subjects off medication and following 6 weeks of haloperidol monotherapy, as well as 15 schizophrenic subjects off medication and following 8 weeks of clozapine monotherapy. The data from these studies will allow evaluation as to whether clozapine, s compared to haloperidol (a typical neuroleptic), selectively occupies extrastriatal dopamine D2 receptors, and whether regional occupancy of D2 receptors can be related to antipsychotic effects. Secondary goals include examining if psychopathological symptom complexes, i.e., positive, negative, and disorganization, as well as cognitive abnormalities in schizophrenia are related to regional levels of D2 receptors.
