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Evaluation of d ‐amphetamine effects on the binding of dopamine D‐2 receptor radioligand, 18 F‐fallypride in nonhuman primates using positron emission tomography
Author(s) -
Mukherjee Jogeshwar,
Yang ZhiYing,
Lew Robert,
Brown Terry,
Kronmal Shara,
Cooper Malcolm D.,
Seiden Lewis S.
Publication year - 1997
Publication title -
synapse
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.809
H-Index - 106
eISSN - 1098-2396
pISSN - 0887-4476
DOI - 10.1002/(sici)1098-2396(199709)27:1<1::aid-syn1>3.0.co;2-9
Subject(s) - radioligand , dopamine , amphetamine , chemistry , binding potential , positron emission tomography , dissociation constant , endocrinology , neuroscience , receptor , psychology , medicine , biochemistry
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, 18 F‐fallypride. In vitro dissociation of 18 F‐fallypride with dopamine in rat striatal homogenates exhibited a dissociation rate, k off , of 1.76 × 10 −2 min −1 while the association rate constant, k on , was found to be 5.30 × 10 8 M −1 min −1 . This resulted in a dissociation constant, K D of 33 pM for 18 F‐fallypride. For in vivo studies, we investigated the effects of reserpine and d ‐amphetamine treatment on 18 F‐fallypride in an attempt to study competition of endogenous dopamine with the radioligand at the receptor sites in rats and monkeys. PET experiments with 18 F‐fallypride in two male rhesus monkeys were carried out in a PETT VI scanner. In control experiments, rapid specific uptake of 18 F‐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 18 F‐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 18 F‐fallypride as well as evidence of an enhanced clearance of specifically bound 18 F‐fallypride after administering AMPH in the two monkeys. The dissociation rates, k off , of 18 F‐fallypride without AMPH was <10 −4 min −1 but after 25 min preadministration of AMPH (1 mg/kg), it was 4.1 × 10 −3 min −1 and after 17, 45 and 90 min postadministration of AMPH (1 mg/kg) it was 3.6 × 10 −3 to 4.0 × 10 −3 min −1 . Lower doses of AMPH (0.25 mg/kg) had a reduced effect on the binding of 18 F‐fallypride. No effect was seen until about 30 minutes after the injection of AMPH. Studies with various doses indicated that 18 F‐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 18 F‐fallypride. Synapse 27:1–13, 1997. © 1997 Wiley‐Liss, Inc.