In:
ChemMedChem, Wiley, Vol. 14, No. 3 ( 2019-02-05), p. 303-309
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1860-7179
,
1860-7187
DOI:
10.1002/cmdc.201800710
Language:
English
Publisher:
Wiley
Publication Date:
2019
detail.hit.zdb_id:
2209649-8
SSG:
15,3
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