Evaluation ofd-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.

Recent methods for measuring dopamine D3 receptor occupancy in vivo: importance for drug development

“…The D2/3 receptors were the first to be imaged using [ 11 C]- N -methylspiperone in the living human brain using PET (Wagner et al, 1983). Since then a number of new radioligands to measure these receptors have been developed, e.g., [ 18 F]-FESP, [ 11 C]-raclopride, [ 11 C]- N -methylbenperidol, [ 11 C]-FLB 457, [ 18 F]-fallypride (Ehrin et al, 1985; Coenen et al, 1987; Suehiro et al, 1990; Halldin et al, 1995; Mukherjee et al, 1997). Since PET imaging measures the binding of a radioligand to a receptor, changes in binding over time can be attributed to up-regulation or down-regulation of the receptor.…”

Timing of moderate level prenatal alcohol exposure influences gene expression of sensory processing behavior in rhesus monkeys

“…Each anesthetized animal was positioned in the ECAT 933 PET scanner with horizontal imaging slices parallel to the orbital-meatus (OM) plane. The tracer used to assess DA D 2 receptors was [ 18 F]-Fallypride ([ 18 F]FAL), an F-18-labeled raclopride analog developed by Mukherjee et al (1997). [ 18 F]FAL was prepared using a procedure adopted from Mukherjee et al (1995).…”

“…Rh5-HTTLPR genotype ( l/l vs. l/s and s/s ) were determined. We also measured striatal DA D 2 R function in positron emission tomography (PET) scans using [ 18 F]-fallypride ([ 18 F]FAL) developed by Mukherjee et al (1997). [ 18 F]FAL is currently the PET tracer of choice for DA D 2 receptor studies because of its optimal imaging properties (Kessler et al, 2009).…”

“…We assessed DA D 2 R availability because the process for assessing this receptor expression is well established from decades of research into neurodegenerative disease such as Parkinson's. The tracer used to assess DA D 2 R availability was [ 18 F]fallypride (FAL), a fluorine-18-labeled raclopride analogue developed by Mukherjee et al (1997). FAL has a high affinity for DA D 2 receptors and high brain uptake, almost three times higher compared with [ 11 C]raclopride.…”

PET Imaging of Dopamine Neurotransmission During EEG Neurofeedback

“…Development of high-affinity radioligands for the D 2/3 receptor such as [ 18 F]Fallypride have enabled noninvasive assessment of extrastriatal D 2/3 receptor densities during pharmacologic (Slifstein et al, 2010) and behavioral paradigms (Albrecht et al, 2014). For example, PET experiments with [ 18 F]Fallypride in monkeys showed that amphetamine challenge may induce a striking reduction in binding in the anterior cingulate cortex (ACC) (Mukherjee et al, 1997). It has also been shown that a single [ 18 F]Fallypride scan protocol and linearized simplified reference region modeling (LSSRM) analysis can be used to measure extrastriatal dopamine release induced by a behavioural task (Christian et al, 2006;Lataster et al, 2011).…”