Evaluation of d-amphetamine effects on the binding of dopamine D-2 receptor radioligand, F-18-fallypride in nonhuman primates using positron emission tomography

We have investigated the ability of dopamine to compete with the binding of the high affinity dopamine D-2 receptor positron emission tomography (PET) radioligand, F-18-fallypride. In vitro dissociation of F-18-fallypride with dopamine in rat striatal homogenates exhibited a dissociation rate, k(off), of 1.76 x 10(-2) min(-1) while the association rate constant, k(on) was found to be 5.30 x 10(8) M-1 min(-1). This resulted in a dissociation constant, K-D of 33 pM for F-18-fallypride. For in vivo studies, we investigated the effects of reserpine and d-amphetamine treatment on F-18-fallypride in an attempt to study competition of endogenous dopamine with the radioligand at the receptor sites in rats and monkeys. PET experiments with F-18-fallypride in two male rhesus monkeys were carried out in a PETT VI scanner In control experiments, rapid specific uptake of F-18-fallypride in the striata was observed (0.05-0.06% injected dose (ID)/g) while nonspecifically bound tracer cleared from other parts of the brain. Striata/cerebellum ratios for F-18-fallypride were approximately 8 at 80 min postinjection; respectively. The monkeys received various doses (0.25 to 1.50 mg/kg) of d-amphetamine (AMPH) pre- and postinjection of the radioligand. There was a decrease of specifically bound F-18-fallypride as well as evidence of an enhanced clearance of specifically bound F-18-fallypride after administering AMPH in the two monkeys. The dissociation rates, k(off), of F-18-fallypride without AMPH was <10(-4) min(-1) but after 25 min preadministration of AMPH (1 mg/kg), it was 4.1 x 10(-3) min(-1) and after 17, 45 and 90 min postadministration of AMPH (1 mg/kg) it was 3.6 x 10(-3) to 4.0 x 10(-3) min(-1). Lower doses of AMPH (0.25 mg/kg) had a reduced effect on the binding of F-18-fallypride. No effect was seen until about 30 minutes after the injection of AMPH. Studies with various doses indicated that F-18-fallypride has a maximum response at doses of 0.75-1.50 mg/kg, with an approximately 16%/hour reduction in binding. These results indicate that AMPH stimulated release of endogenous dopamine reduces the specific binding of F-18-fallypride. (C) 1997 Wiley-Liss, Inc.