[¹¹C]AF150(S): An agonist PET ligand for the M1 muscarinic acetylcholine receptor

Objectives The G protein coupled M1 muscarinic acetylcholine receptor (M1ACh-R) is the muscarinic subtype with the highest density in the brain. The aim of this study was to investigate the labelled selective M1ACh-R agonist [¹¹C]AF150(S) as a putative agonist PET ligand.

Methods Following IV administration, the time course and regional distribution of [¹¹C]AF150(S) in rat brain was assessed using PET. Dynamic PET scans were acquired on a HRRT scanner (CTI/Siemens). Additional PET scans in the same rats were performed after pre-treatment with the M1ACh-R antagonists, pirenzepine and trihexyphenidyl, and the M4/M1ACh-R agonist xanomeline. Finally, predosing with haloperidol was used to asses potential binding of [¹¹C]AF150(S) to σ sites.

Results Uptake of [¹¹C]AF150(S) was higher in M1ACh-Rs rich areas, such as striatum and cerebral cortex, than in M1ACh-Rs poor regions, like cerebellum and medulla oblongata. The highest regional-to-cerebellar ratios were 1.35 and 1.20 for striatum and cerebral cortex, respectively. Pirenzepine and trihexyphenidyl caused the largest reductions in cerebral cortex (24-28%) and striatum (19-22%). Reductions by xanomeline were less pronounced, possibly because the applied dose was too low. Haloperidol produced a reduction in striatum (22%), probably due to haloperidol mediated enhanced acetylcholine release as a result of dopamine D₂ receptor blockade.

Conclusions The agonist ligand [¹¹C]AF150(S) provides a small, but significant, M1ACh-R related signal in vivo, warranting further evaluation as a putative PET tracer for in vivo imaging of M1ACh-R.

Research Support The A.J. Coops foundation for financial support of this study