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Synthesis and Preliminary Evaluation of 11 C‐Labeled VU0467485/AZ13713945 and Its Analogues for Imaging Muscarinic Acetylcholine Receptor Subtype 4
Author(s) -
Deng Xiaoyun,
Hatori Akiko,
Chen Zhen,
Kumata Katsushi,
Shao Tuo,
Zhang Xiaofei,
Yamasaki Tomoteru,
Hu Kuan,
Yu Qingzhen,
Ma Longle,
Wang Gangqiang,
Wang Lu,
Shao Yihan,
Josephson Lee,
Sun Shaofa,
Zhang MingRong,
Liang Steven
Publication year - 2019
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201800710
Subject(s) - muscarinic acetylcholine receptor , allosteric regulation , acetylcholine , allosteric modulator , chemistry , acetylcholine receptor , agonist , pharmacology , in vitro , receptor , cholinergic , biophysics , neuroscience , stereochemistry , biochemistry , medicine , biology
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 11 C‐labeled positron emission tomography (PET) ligands based on a validated M 4 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 M 4 R. Nevertheless, further physiochemical property optimization is necessary to overcome the challenges associated with limited brain permeability.