Pet Imaging of Extrastriatial Dopamine Levels

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DESCRIPTION (provided by applicant): Dopaminergic neurotransmission in cortex, limbic regions and thalamus is believed to be centrally involved in the pathophysiology of schizophrenia, psychostimulant drug abuse, and attention deficit disorder. While there are PET and SPECT methods for evaluating striatal dopamine (DA) release and baseline extracellular DA levels in man, at present there are no well validated methods for studying DA release and baseline extracellular DA levels in extrastriatal regions in man. [18F] fallypride is an extremely potent and selective dopamine D2 radioligand, i.e., a KD of 31 pM for the dopamine D2 receptor, which can be used do delineate and quantitate striatal, thalamic, limbic and cortical dopamine D2 receptors in man. Studies in primates demonstrate that [18F] fallypride is sensitive to levels of d-amphetamine released dopamine in both striatum and extrastriatal regions. We propose to perform [18F] fallypride PET studies in 12 normal subjects (ages 18-40, 6M, 6F) prior to and following d-amphetamine administration (0.43mg/kg orally) to study d-amphetamine induced dopamine release in extrastriatal regions. This dose of real d-amphetamine produces decrements in striatal [11C] raclopride binding potentials similar to those seen with a 0.2-0.3 mg/kg IV dose of d-amphetamine with similar variability, but with fewer and less severe side effects. We propose to perform additional [18F] fallypride PET studies in 12 normal subjects (ages 18-40, 6M, 6F) prior to and following a 36-hour course of 56.6 mg/kg alphamethylparatyrosine/24 hours (6 grams over 36 hours for a 70 kg subject) to estimate baseline extracellular dopamine levels in extrastriatal regions. The development of methods for estimating DA release and baseline extracellular DA levels in extrastriatal regions will allow important new research studies in a number of psychiatric and neurological disorders which may allow design and evaluation of new therapeutic interventions.