Pharmacological characterization and positron emission tomography evaluation of 4-[76Br]bromodexetimide and 4-[76Br]bromolevetimide for investigations of central muscarinic cholinergic receptors

Abstract 4-[ 76 Br]bromodexetimide and its inactive enantiomer 4-[ 76 Br]bromolevetimide were prepared via electrophilic bromodesilylation using chloramine-T and no-carrier-added (NCA) [ 76 Br]NH 4 . In vitro , B max measured on rat cortex membranes were 3.7 ± 0.2 and 76 Br]bromodexetimide and 4-[ 76 Br]bromolevetimide, respectively. The k D of 4-[ 76 Br]bromodexetimide was 1.9 ± 0.3 nM. In vivo studies in rats showed specific uptake of 4-[ 76 Br]bromodexetimide in cortex, striatum, thalamus and hippocampus. No specific uptake was observed with 4-[ 76 Br]bromolevetimide. With [ 76 Br]bromodexetimide, positron emission tomography (PET) studies in primates demonstrated a preferential accumulation of the radioactivity in the cortex and striatum which was displaced to the level of cerebellum by dexetimide. With 4-[ 76 Br]bromolevetimide, the radioactivity concentrations in the cortex and striatum were similar to that of cerebellum.