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

Authors
  • Deng, Xiaoyun1
  • Hatori, Akiko2
  • Chen, Zhen1
  • Kumata, Katsushi2
  • Shao, Tuo1
  • Zhang, Xiaofei1
  • Yamasaki, Tomoteru2
  • Hu, Kuan2
  • Yu, Qingzhen1
  • Ma, Longle1
  • Wang, Gangqiang3
  • Wang, Lu1, 4
  • Shao, Yihan5
  • Josephson, Lee1
  • Sun, Shaofa3
  • Zhang, Ming-Rong2
  • Liang, Steven1
  • 1 Department of Radiology, Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.
  • 2 Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, 263-8555, Japan. , (Japan)
  • 3 Hubei Collaborative Innovation Centre for Non-power Nuclear Technology, College of Nuclear Technology & Chemistry and Biology, Hubei University of Science and Technology, Xianning, China. , (China)
  • 4 Department of Nuclear Medicine and PET/CT-MRI Center, the First Affiliated Hospital of Jinan University & Institute of Molecular and Functional Imaging, Jinan University, Guangzhou, 510630, China. , (China)
  • 5 Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK, 73019, USA.
Type
Published Article
Journal
ChemMedChem
Publisher
Wiley (John Wiley & Sons)
Publication Date
Feb 05, 2019
Volume
14
Issue
3
Pages
303–309
Identifiers
DOI: 10.1002/cmdc.201800710
PMID: 30589226
Source
Medline
Keywords
Language
English
License
Unknown

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. © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

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