Abstract
496
Objectives PET studies with D2/3 radiotracers such as [11C]raclopride and [18F]fallypride display an increase in binding potential (BP) under conditions of dopamine (DA) depletion. However, the low selectivity of these ligands for D2 vs. D3 receptors renders it impossible to determine which DA receptor subtype is responsible for this increased radiotracer binding. Our group has developed two radiolabeled DA partial agonists, [18F]LS-3134 (D3 = 0.17 nM; D2 = 28 nM) and [11C]SV-3130 (D2 = 0.22 nM; D3 = 13 nM), which display a 160-fold selectivity for D3 and 60-fold selectivity for D2 receptors. We recently reported that DA depletion produced an increase in the D3 BP of [18F]LS-3134 in rhesus brain (Synapse, in press). The goal of this study was to determine the effect of DA depletion on the BP of [11C]SV-3130 to D2 receptors.
Methods PET imaging studies were conducted with [11C]SV-3130 and [18F]LS-3134 in adult male rhesus monkeys (N = 4) under baseline and DA depletion conditions (1 mg/kg lorazepam i.v. 30 min prior to radiotracer injection). Regions-of-interest were drawn around the caudate, putamen, and thalamus and tissue-time activity curves were constructed. The BP for each ROI was calculated using Logan analysis.
Results Lorazepam caused a non-significant decrease in the D2 BP of [11C]SV-3130 in the caudate and putamen (caudate: 1.86 ± 0.02 vs. 1.57 ± 0.33; putamen: 1.98 ± 0.11 vs. 1.69 ± 0.33). In contrast, it was not possible to image D3 receptors with [18F]LS-3134 without the lorazepam pretreatment (caudate: -0.07 ± 0.02 vs. 0.14 ± 0.05; putamen: -0.04 ± 0.02 vs. 0.22 ± 0.02; thalamus: -0.02 ± 0.01 vs. 0.24 ± 0.06).
Conclusions Our results suggest that there is a high in vivo occupancy of D3 receptors by endogenous DA, whereas D2 receptors appear to be unoccupied by DA. These results may imply that DA depletion increases BP of nonselective D2/3 radiotracers such as [11C]raclopride and [18F]fallypride by increasing D3 availability.
Research Support MH81281 and DA2984