Endogenous dopamine (DA) competes with the binding of a radiolabeled D₃ receptor partial agonist in vivo: a positron emission tomography study

Abstract

A series of microPET imaging studies were conducted in anesthetized rhesus monkeys using the dopamine D₃-selective partial agonist, [¹⁸F]5. There was variable uptake in regions of brain known to express a high density of D₃ receptors under baseline conditions. Pretreatment with lorazepam (1 mg/kg, i.v. 30 min) to reduce endogenous dopamine activity before tracer injection resulted in a dramatic increase in uptake in the caudate, putamen, and thalamus, and an increase in the binding potential (BP) values, a measure of D₃ receptor binding in vivo. These data indicate that there is a high level of competition between [¹⁸F]5 and endogenous dopamine for D₃ receptors in vivo.

Figure 1

Structures of D₃-selective ligands reported in the literature.

Figure 2

Radiosynthesis of [¹⁸F]5.

Figure 3

MicroPET imaging studies of [¹⁸F]5 in rhesus monkeys.

Figure 4

Blood and Tissue time-activity curves (TACs) of [¹⁸F]5 in from microPET imaging studies.. A and B show regional brain TACs from baseline and lorazepam studies. The uptake of [¹⁸F]5 in the representative monkey brain regions (caudate, putamen, cerebellum, and thalamus) reached peak accumulation in the caudate and putamen 5 min post-i.v. injection. Lorazepam (1 mg/kg/i.v.) treatment increased [¹⁸F]5 uptake in the caudate, putamen and thalamus. C shows that lorazepam treatment did not change the arterial blood TAC compared to baseline data. The inset graph shows that there was also no change during the initial 5 minutes.

Figure 5

Binding potential (BP) analysis in caudate, putamen and thalamus of microPET scans from baseline lorazepam treatment and blocking studies (under lorazepam). Blocking with Compound 6 (1 mg/kg/i.v.) significantly decreased [¹⁸F]5 binding potential in striatal regions: caudate (p < 0.05), putamen (p < 0.001) and extra-striatal regions: thalamus (p < 0.005).