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.

Evaluation of Dopamine D-2 Receptor Occupancy by Clozapine, Risperidone, and Haloperidol In Vivo in the Rodent and Nonhuman Primate Brain Using 18F-Fallypride

“…We have previously shown that binding of 18 F-fallypride is not significantly altered in reserpinized rats compared to control rats, suggesting that basal levels of dopamine has little affect on 18 F-fallypride binding to D-2 receptors (Mukherjee et al 1997). However, when the concentration of dopamine is increased by pharmacological challenges of d-amphetamine, displacement of 18 F-fallypride is observed.…”

Sensory Processing Disorder in a Primate Model: Evidence From a Longitudinal Study of Prenatal Alcohol and Prenatal Stress Effects

“…DA synthesis was assessed using FMT as a PET tracer (DeJesus, Endres, Shelton, Nickles, & Holden, 1997). The tracer used to assess D 2 receptors was FAL, an F-18-labeled raclopride analog developed by Mukherjee et al (1997); 5 mCi in 1-5 ml normal saline of either FAL or FMT were administered as an intravenous bolus and a dynamic sequence of images over 90 min, including a total of 13 frames with duration increasing from 2 to 10 min was collected. At the end of scanning, the animals were extubated, allowed to awaken, and then returned to the animal care facility.…”

“…The striatum is rich in dopaminergic innervation and is part of the basal ganglia thalamo-cortical loop involved in behavioral inhibition (Casey, 2001 (Mukherjee et al, 1997;Schneider et al, 2005).…”

Amphetamine-Induced Displacement of [18F] Fallypride in Striatum and Extrastriatal Regions in Humans

“…The striatal uptakes of [ Olsson et al, 1999;Fujita et al, 1999), making estimation of striatal DA D 2 /D 3 receptor levels difficult. [ 18 F]fallypride is a benzamide with very high-affinity for DA D 2 /D 3 receptors, which has been used to visualize and quantify levels of striatal and extrastriatal DA D 2 /D 3 receptors using positron emission tomography (PET) (Mukherjee et al, 1999Rieck et al, 2004 (Mukherjee et al, 1997;Kessler et al, 1991;Olsson et al, 1999Olsson et al, , 2004Christian et al, 2004).…”