Radiosynthesis and biological evaluation of the M1 muscarinic acetylcholine receptor agonist ligand [11C]AF150(S)

Abstract

Purpose M1 muscarinic acetylcholine receptor (M1ACh-R) agonists are potential therapeutics for cognitive disorders. The aim of this study was to develop an orthosteric agonist positron emission tomography (PET) ligand for the M1ACh-R that would provide a tool to explore the active G-protein coupled receptor. To that extend, the radiosynthesis, receptor binding in vitro, and brain uptake of [11C]AF150(S), a selective M1ACh-R agonist, were investigated. Procedures [11C]AF150(S) was synthesized, its binding properties were investigated using autoradiography on rat brain sections, and brain uptake was determined in biodistribution studies ex vivo in rats. Metabolites in brain and blood were measured using high-performance liquid chromatography. Results Yield of the [11C]AF150(S) radiosynthesis was 69 ± 9% with radiochemical purity >99%. The logDoct,7.4 was 0.05. Autoradiography showed binding in M1ACh-R rich brain areas and selective inhibition by muscarinic agents in conditions promoting agonist binding. Biodistribution studies revealed rapid and high brain uptake, to levels exceeding five times the blood level. In M1ACh-R rich areas, specific uptake versus cerebellum was apparent, remaining constant over 60 min in spite of rapid decline of radioactivity from the brain and rapid peripheral metabolism. Brain uptake of [11C]AF150(S) may involve facilitated transport. Conclusion [11C]AF150(S) was successfully synthesized, showed M1ACh-R agonist binding properties, and high brain uptake. It provides an interesting lead for the development of an M1ACh-R agonist PET ligand meant to explore the active receptor state. Copyright © 2012 John Wiley & Sons, Ltd.