The role of species-dependent metabolism in the regional brain retention of 18F-labeled muscarinic acetylcholine receptor ligands

We have developed PET radioligands for the muscarinic acetylcholine receptor designed to be sensitive to endogenous acetylcholine changes. These radioligands were based on the piperidyl and pyrrolidyl benzilate scaffold and include (R)-N-(2- [F-18]fluoroethyl)-3-piperidyl benzilate (1b), (R)-N-(2-[F-18]fluoroethyl)-3-pyrrolidyl benzilate (2b), and N-(2-[F-18]fluoroethyl)-4-piperidyl benzilate (3b). In the mouse, intravenous injection of 2b produced a heterogeneous receptor-mediated regional retention of radioactivity, whereas in the rat a homogeneous brain distribution was observed. Analyses of blood and brain extracts showed a radiolabeled metabolite for 2b which was formed to a much greater extent in mice than rats. This metabolite may have a higher receptor binding affinity than authentic 2b, and thus be responsible for the apparent receptor-mediated binding in the mouse brain. Our findings emphasize the importance of metabolite analysis in multiple species when developing novel radiopharmaceuticals for in vivo use. (C) 2001 Elsevier Science Inc. All rights reserved.