The purpose of this work is to develop procedures with monkeys for quantification of dopamine receptor occupancy and dopamine release using positron emission tomography (PET) and 11C-raclopride. Two types of studies have been performed to date: bolus injections and a bolus plus infusion (B/I) protocol. Bolus injections of tracer, followed by serial PET scanning and blood sampling with metabolite determinations by HPLC 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 states and following administration of amphetamine (which produces a transient increase in tissue dopamine) demonstrated 20 to 40 percent reduction in raclopride binding. B/I studies produced comparable values for VD as the bolus, although there was a trend toward a smaller release of amphetamine. The paper describing this work has been submitted for publication. Subsequently, PET studies were combined with in vivo microdialysis for measurement of dopamine and raclopride levels. Modeling studies were performed to determine if the standard approach could be extended to incorporate the microdialysis data. Satisfactory agreement was found, and an estimate of the KD of dopamine could be determined. Simulations based on the extended model showed that the measured change in specific binding of raclopride from patient studies is linearly proportional to the magnitude of pulse of dopamine released by amphetamine. The manuscript describing these results is currently in preparation.
