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

Abstract

Muscarinic acetylcholine receptors (mAChRs) have five distinct subunits (M₁ -M₅ ) 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 M₁ /M₄ -preferring agonist, in patients of schizophrenia and Alzheimer's disease, M₁ - or M₄ -selective mAChR modulators have been developed that target the topographically distinct allosteric sites. Herein we report the synthesis and preliminary evaluation of ¹¹ C-labeled positron emission tomography (PET) ligands based on a validated M₄ R positive allosteric modulator VU0467485 (AZ13713945) to facilitate drug discovery. [¹¹ C]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 μmol^-1 ). In vitro autoradiography studies indicated that these three ligands possess moderate-to-high in vitro specific binding to M₄ R. Nevertheless, further physiochemical property optimization is necessary to overcome the challenges associated with limited brain permeability.

Keywords: VU0467485/AZ13713945; carbon-11; muscarinic acetylcholine receptor subtype 4; positive allosteric modulator; positron emission tomography.