Synthesis and Preliminary Evaluation of 11C-Labeled VU0467485/AZ13713945 and Its Analogues for Imaging Muscarinic Acetylcholine Receptor Subtype 4

Muscarinic acetylcholine receptors (mAChRs) have five distinct subunits (M-1-M-5) and are involved in the action of the neurotransmitter acetylcholine in the central and peripheral nervous system. Attributed to the promising clinical efficacy of xanomeline, an M-1/M-4-preferring agonist, in patients of schizophrenia and Alzheimer's disease, M-1- or M-4-selective mAChR modulators have been developed that target the topographically distinct allosteric sites. Herein we report the synthesis and preliminary evaluation of C-11-labeled positron emission tomography (PET) ligands based on a validated M4R positive allosteric modulator VU0467485 (AZ13713945) to facilitate drug discovery. [C-11]VU0467485 and two other ligands were prepared in high radiochemical yields (>30 %, decay-corrected) with high radiochemical purity (>99 %) and high molar activity (>74 GBq mu mol(-1)). In vitro autoradiography studies indicated that these three ligands possess moderate-to-high in vitro specific binding to M4R. Nevertheless, further physiochemical property optimization is necessary to overcome the challenges associated with limited brain permeability.