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Imaging drug-induced dopamine release in rhesus monkeys with [11C]PHNO versus [11C]raclopride PET
NRM2010 abstracts — Poster presentations
Poster Presentation No.: P022
S79
Synaptic Imaging
Imaging drug-induced dopamine release in rhesus monkeys with [11C]PHNO versus [11C]raclopride PET Kelly Cosgrove, Jean-Dominique Gallezot, David Weinzimmer, Krista Fowles, David Labaree, Ming-Qiang Zheng, Keunpoong Lim, Richard Carson, Evan Morris Yale PET Center, Yale University School of Medicine, New Haven, USA Objective: The radiotracer [11C]PHNO may have advantages over other dopamine D2/D3 receptor ligands because as an agonist it measures only the high affinity—functionally active—D2/D3 receptors and not the low affinity receptors. Ginovart et al. (2006) demonstrated improved sensitivity over [11C]raclopride for measuring amphetamine-induced changes in synaptic dopamine levels. Our aim was to take advantage of the strength of [11C]PHNO for measuring the small dopamine signal induced by nicotine. Previously, Marenco et al. (2004) reported that a nicotine challenge (0.01–0.06 mg/kg, IV) yielded a 5% reduction and an amphetamine challenge (0.4 mg/kg, IV) in a 28% reduction in [11C]raclopride binding potential in the caudate and putamen in monkeys. The goal of this study was to compare the sensitivity of [11C]PHNO PET to that of [11C] raclopride PET with nicotine- and amphetamine-induced dopamine release in nonhuman primates. Methods: Two adult male rhesus monkeys have been imaged on a FOCUS 220 PET scanner after injection of a bolus of [11C]PHNO or [11C] raclopride in 3 conditions: baseline; pre-injection of nicotine (0.1 mg/kg bolus + 0.07 mg/kg infusion over 30 min); and pre-injection of amphetamine (0.4 mg/kg, 5 min prior to radiotracer injection). The mass dose of each radiotracer was held constant within each animal between scans. Four other animals participated in test–retest studies with bolus injections of [11C]PHNO on two separate days with the mass dose of PHNO kept constant at 0.1 µg/kg. Dopamine release was measured as change in binding potential (BPND). BPND was estimated with SRTM using the cerebellum as the reference region. Results: Average test–retest variability in [11C]PHNO in caudate and putamen was 6%. With [11C]PHNO, nicotine administration resulted in an average change of −7.5 ± 13.4% in BPND in the caudate and −7.0 ± 1.4% decrease in the putamen. Amphetamine administration resulted in a robust change of −48.5 ± 2.1% in the caudate and −49.5 ± 4.9% in the putamen. With [11C]raclopride there was a nicotine-induced change in BPND of +3.0 + 1.4% in the caudate and −8.5 ± 4.9% in the putamen. Amphetamine administration resulted in a change of −43.5 ± 19.1% in the caudate and −42.5 ± 9.2% in the putamen. Conclusions: Our preliminary results do not support a substantive improvement in sensitivity to drug-induced dopamine release for [11C]PHNO over [11C]raclopride in the caudate and putamen. We are currently investigating the utility of PHNO in predominantly D3 regions in our animals as well as increasing our sample size.
doi:10.1016/j.neuroimage.2010.04.063
Poster Presentation No.: P022
S79
Synaptic Imaging
Imaging drug-induced dopamine release in rhesus monkeys with [11C]PHNO versus [11C]raclopride PET Kelly Cosgrove, Jean-Dominique Gallezot, David Weinzimmer, Krista Fowles, David Labaree, Ming-Qiang Zheng, Keunpoong Lim, Richard Carson, Evan Morris Yale PET Center, Yale University School of Medicine, New Haven, USA Objective: The radiotracer [11C]PHNO may have advantages over other dopamine D2/D3 receptor ligands because as an agonist it measures only the high affinity—functionally active—D2/D3 receptors and not the low affinity receptors. Ginovart et al. (2006) demonstrated improved sensitivity over [11C]raclopride for measuring amphetamine-induced changes in synaptic dopamine levels. Our aim was to take advantage of the strength of [11C]PHNO for measuring the small dopamine signal induced by nicotine. Previously, Marenco et al. (2004) reported that a nicotine challenge (0.01–0.06 mg/kg, IV) yielded a 5% reduction and an amphetamine challenge (0.4 mg/kg, IV) in a 28% reduction in [11C]raclopride binding potential in the caudate and putamen in monkeys. The goal of this study was to compare the sensitivity of [11C]PHNO PET to that of [11C] raclopride PET with nicotine- and amphetamine-induced dopamine release in nonhuman primates. Methods: Two adult male rhesus monkeys have been imaged on a FOCUS 220 PET scanner after injection of a bolus of [11C]PHNO or [11C] raclopride in 3 conditions: baseline; pre-injection of nicotine (0.1 mg/kg bolus + 0.07 mg/kg infusion over 30 min); and pre-injection of amphetamine (0.4 mg/kg, 5 min prior to radiotracer injection). The mass dose of each radiotracer was held constant within each animal between scans. Four other animals participated in test–retest studies with bolus injections of [11C]PHNO on two separate days with the mass dose of PHNO kept constant at 0.1 µg/kg. Dopamine release was measured as change in binding potential (BPND). BPND was estimated with SRTM using the cerebellum as the reference region. Results: Average test–retest variability in [11C]PHNO in caudate and putamen was 6%. With [11C]PHNO, nicotine administration resulted in an average change of −7.5 ± 13.4% in BPND in the caudate and −7.0 ± 1.4% decrease in the putamen. Amphetamine administration resulted in a robust change of −48.5 ± 2.1% in the caudate and −49.5 ± 4.9% in the putamen. With [11C]raclopride there was a nicotine-induced change in BPND of +3.0 + 1.4% in the caudate and −8.5 ± 4.9% in the putamen. Amphetamine administration resulted in a change of −43.5 ± 19.1% in the caudate and −42.5 ± 9.2% in the putamen. Conclusions: Our preliminary results do not support a substantive improvement in sensitivity to drug-induced dopamine release for [11C]PHNO over [11C]raclopride in the caudate and putamen. We are currently investigating the utility of PHNO in predominantly D3 regions in our animals as well as increasing our sample size.
doi:10.1016/j.neuroimage.2010.04.063