COMPARISON OF 2 F-18 LABELED BENZAMIDE DERIVATIVES THAT BIND REVERSIBLY TO DOPAMINE D2 RECEPTORS - IN-VITRO BINDING-STUDIES AND POSITION EMISSION TOMOGRAPHY

The purpose of the present set of studies was to characterize, in vitr o an in vivo, two benzamide analogues, ethoxy-N-[1,4-fluorobenzyl)pipe ridin-4yl[benzamide (MBP) and 4'-fluoroclebopride (FCP), for studying dopamine D-2 receptors with Positron Emission Tomography (PET). In vit ro binding studies were conducted to determine the affinities of MBP a nd FCP to the three subtypes of dopamine D-2 receptors: D-2(long), D-3 , and D-4 receptors. MBP was found to have a high affinity (K-i = 1-8 nM) for all three subtypes of the D-2 receptor, whereas FCP had nanomo lar affinity (K-i - 5.5 nM) for D-2(long), and D-3 receptors, and a lo wer affinity for D-4 receptors (K-i = 144 nM). In vitro binding studie s also revealed that MBP had a relatively high affinity for sigma(1) r eceptors (K-i = 11 nM) compared to FCP (K-i = 340 nM). PET imaging stu dies were conducted in rhesus monkeys with fluorine-18 labeled analogu es of each compound. Both [F-18]MBP and [F-18]FCP displayed reversible binding kinetics during the 3 h time course of PET. [F-18]FCP was fou nd to have a higher basal ganglia:cerebellum ratio and lower variabili ty in the rate of washout from D-2 receptors in vivo relative to [F-18 ]MBP. Neither radiotracer was found to produce radiolabled metabolites capable of crossing the blood-brain barrier. The high sigma(1) bindin g affinity and low basal ganglia:cerebellum ratio of [F-18]MBP indicat e that this ligand may not be suitable for quantitative studies of D-2 receptors. The results from the in vitro and in vivo studies indicate that [F-18]FCP is a promising ligand for studying D-2 receptors with PET. (C) 1996 Wiley-Liss, Inc.