Dopaminergic (DA) modulation of brain function is disturbed in several disabling psychiatric disorders and represents the target of key psychopharmacologic agents, such as neuroleptics. Schizophrenia has been considered a prototype of dysregulated DA signaling, with associated prefrontal cortex (PFC) dysfunction. Prevailing views attribute key symptoms of schizophrenia to deficient DA signaling within mesocortical DA tracts. Little is known, however, about the pre-, intra-, and post-synaptic processes that contribute to dopaminergic dysregulation. Regional cortical DA activity, critical to these processes, has been difficult to measure in patients with the available imaging techniques. The current clinical study aims to address this open issue by taking advantage of two recently developed positron emission tomography (PET) radioligands, [(11)C]NNC-112 and [(18)F]Fallypride, that bind differentially and with a higher binding potential (BP) than previous compounds to the D(1) (NNC-112) or D(2/3) (fallypride) receptors. By measuring the regional BP of these two compounds, cortical and subcortical DA receptor anomalies will be characterized in schizophrenia. Within the Clinical Brain Disorders Branch (CBDB), this PET protocol is expected to add crucial information about DA receptor status to ongoing regional cerebral blood flow (rCBF), magnetic resonance imaging (MRI), magneto-encephalography (MEG) and genetic studies. It will lead to an improved understanding of the modulatory influence of DA on frontal lobe functioning and facilitate the study of how genetic polymorphisms interact with regional changes in D(1) and D(2/3) receptors to increase the risk for schizophrenia.