title: Evaluation of d-amphetamine effects on the binding of dopamine D-2 receptor radioligand, 18F-fallypride in nonhuman primates using positron emission tomography.
abstract: We have investigated the ability of dopamine to compete with the binding of the high affinity dopamine D2 receptor positron emission tomography (PET) radioligand, 18F-fallypride. In vitro dissociation of 18F-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 18F-fallypride. For in vivo studies, we investigated the effects of reserpine and d-amphetamine treatment on 18F-fallypride in an attempt to study competition of endogenous dopamine with the radioligand at the receptor sites in rats and monkeys. PET experiments with 18F-fallypride in two male rhesus monkeys were carried out in a PETT VI scanner. In control experiments, rapid specific uptake of 18F-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 18F-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 18F-fallypride as well as evidence of an enhanced clearance of specifically bound 18F-fallypride after administering AMPH in the two monkeys. The dissociation rates, k(off), of 18F-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 18F-fallypride. No effect was seen until about 30 minutes after the injection of AMPH. Studies with various doses indicated that 18F-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 18F-fallypride.
authors.affiliation: Franklin McLean Institute, Department of Radiology, University of Chicago, Illinois 60637, USA. j-mukherjee@uchicago.edu
authors.forename: J
authors.initials: J
authors.lastname: Mukherjee
authors.forename: Z Y
authors.initials: ZY
authors.lastname: Yang
authors.forename: R
authors.initials: R
authors.lastname: Lew
authors.forename: T
authors.initials: T
authors.lastname: Brown
authors.forename: S
authors.initials: S
authors.lastname: Kronmal
authors.forename: M D
authors.initials: MD
authors.lastname: Cooper
authors.forename: L S
authors.initials: LS
authors.lastname: Seiden
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects; D003913:Dextroamphetamine / Q000494:pharmacology*; D004298:Dopamine / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000494:pharmacology; D008251:Macaca; D008297:Male; D011859:Radiography; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000187:drug effects*; D014055:Tomography, Emission-Computed
chemical_list: D018492:Dopamine Antagonists; D017448:Receptors, Dopamine D2; D006220:Haloperidol; D003913:Dextroamphetamine; D004298:Dopamine