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 bindi ng of the high affinity dopamine D-2 receptor positron emission tomogr aphy (PET) radioligand, F-18-fallypride. In vitro dissociation of F-18 -fallypride with dopamine in rat striatal homogenates exhibited a diss ociation 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 re sulted in a dissociation constant, K-D of 33 pM for F-18-fallypride. F or in vivo studies, we investigated the effects of reserpine and d-amp hetamine treatment on F-18-fallypride in an attempt to study competiti on of endogenous dopamine with the radioligand at the receptor sites i n rats and monkeys. PET experiments with F-18-fallypride in two male r hesus monkeys were carried out in a PETT VI scanner In control experim ents, rapid specific uptake of F-18-fallypride in the striata was obse rved (0.05-0.06% injected dose (ID)/g) while nonspecifically bound tra cer cleared from other parts of the brain. Striata/cerebellum ratios f or F-18-fallypride were approximately 8 at 80 min postinjection; respe ctively. The monkeys received various doses (0.25 to 1.50 mg/kg) of d- amphetamine (AMPH) pre- and postinjection of the radioligand. There wa s 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 a fter 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) ha d a reduced effect on the binding of F-18-fallypride. No effect was se en until about 30 minutes after the injection of AMPH. Studies with va rious doses indicated that F-18-fallypride has a maximum response at d oses of 0.75-1.50 mg/kg, with an approximately 16%/hour reduction in b inding. These results indicate that AMPH stimulated release of endogen ous dopamine reduces the specific binding of F-18-fallypride. (C) 1997 Wiley-Liss, Inc.