The purpose of this work is to develop procedures with monkeys for quantification of dopamine receptor occupancy and dopamine release using PET and 11C-raclopride. Two types of studies have been performed to date. Initial studies used bolus injections of tracer, followed by serial PET scanning and blood sampling with metabolite determinations by HPLC. These data permit the quantification of the tissue volume of distribution (VD), a measure of total tissue binding (free, nonspecifically bound, and specifically bound tracer). Comparison of the measured VD values between control state and following administration of amphetamine (which produces pre-synaptic release of dopamine) demonstrated 20-40% reduction in raclopride binding. The next phase of study used a bolus plus infusion protocol to produce true equilibrium to allow measurement of the time course of raclopride displacement following amphetamine. These studies produced comparable values for VD as the bolus although there was a trend towards a smaller release of amphetamine. Subsequently, PET studies were combined with in vivo microdialysis for measurement of dopamine and raclopride levels. Modeling studies are underway to address the following questions: 1. What model configurations provide agreement between the measured PET and microdialysis data? 2. Will bolus or infusion methods provide different measures of neurotransmitter release? 3. What are the optimal tracer characteristics to measure the magnitude and time course of neurotransmitter release?
