[(11)C]AF150(S), an agonist PET ligand for M1 muscarinic acetylcholine receptors

BACKGROUND: The M1 muscarinic acetylcholine receptor (M1ACh-R) is a G protein-coupled receptor that can occur in interconvertible coupled and uncoupled states. It is enriched in the basal ganglia, hippocampus, olfactory bulb, and cortical areas, and plays a role in motor and cognitive functions. Muscarinic M1 agonists are potential therapeutic agents for cognitive disorders. The aim of this study was to evaluate [(11)C]AF150(S) as a putative M1ACh-R agonist PET ligand, which, owing to its agonist properties, could provide a tool to explore the active G protein-coupled receptor. METHODS: Regional kinetics of [(11)C]AF150(S) in rat brain were measured using a high-resolution research tomograph, both under baseline conditions and following pre-treatment with various compounds or co-administration of non-radioactive AF150(S). Data were analysed by calculating standard uptake values and by applying the simplified reference tissue model (SRTM). RESULTS: [(11)C]AF150(S) was rapidly taken up in the brain, followed by a rapid clearance from all brain regions. Analysis of PET data using SRTM revealed a binding potential (BP(ND)) of 0.25 for the striatum, 0.20 for the hippocampus, 0.16 for the frontal cortical area and 0.15 for the posterior cortical area, all regions rich in M1ACh-R. BP(ND) values were significantly reduced following pre-treatment with M1ACh-R antagonists. BP(ND) values were not affected by pre-treatment with a M3ACh-R antagonist. Moreover, BP(ND) was significantly reduced after pre-treatment with haloperidol, a dopamine D(2) receptor blocker that causes an increase in extracellular acetylcholine (ACh). The latter may compete with [(11)C]AF150(S) for binding to the M1ACh-R; further pharmacological agents were applied to investigate this possibility. Upon injection of the highest dose (49.1 nmol kg(−1)) of [(11)C]AF150(S) diluted with non-radioactive AF150(S), brain concentration of AF150(S) reached 100 nmol L(−1) at peak level. At this concentration, no sign of saturation in binding to M1ACh-R was observed. CONCLUSIONS: The agonist PET ligand [(11)C]AF150(S) was rapidly taken up in the brain and showed an apparent specific M1ACh-R-related signal in brain areas that are rich in M1ACh-R. Moreover, binding of the agonist PET ligand [(11)C]AF150(S) appears to be sensitive to changes in extracellular ACh levels. Further studies are needed to evaluate the full potential of [(11)C]AF150(S) for imaging the active pool of M1ACh-R in vivo.