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

Muscarinic acetylcholine receptors (mAChRs) have five distinct subunits (M–M) 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/M‐preferring agonist, in patients of schi... Full description

Journal Title: ChemMedChem February 5, 2019, Vol.14(3), pp.303-309
Main Author: Deng, Xiaoyun
Other Authors: 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, Ming-Rong , Liang, Steven
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1860-7187 ; DOI: 10.1002/cmdc.201800710
Link: http://search.proquest.com/docview/2161063634/?pq-origsite=primo
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title: Synthesis and Preliminary Evaluation of 11 C-Labeled VU0467485/AZ13713945 and Its Analogues for Imaging Muscarinic Acetylcholine Receptor Subtype 4.
format: Article
creator:
  • 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, Ming-Rong
  • Liang, Steven
subjects:
  • Animals–Diagnostic Imaging
  • Brain–Chemical Synthesis
  • Carbon Radioisotopes–Chemistry
  • Ligands–Pharmacology
  • Molecular Structure–Chemical Synthesis
  • Muscarinic Agonists–Chemistry
  • Positron-Emission Tomography–Pharmacology
  • Pyridazines–Agonists
  • Rats–Analysis
  • Receptor, Muscarinic M4–Analysis
  • Carbon Radioisotopes
  • Carbon-11
  • Ligands
  • Muscarinic Agonists
  • Pyridazines
  • Receptor, Muscarinic M4
  • Vu0467485
  • Vu0467485/Az13713945
  • Carbon-11
  • Muscarinic Acetylcholine Receptor Subtype 4
ispartof: ChemMedChem, February 5, 2019, Vol.14(3), pp.303-309
description: Muscarinic acetylcholine receptors (mAChRs) have five distinct subunits (M–M) 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/M‐preferring agonist, in patients of schizophrenia and Alzheimer's disease, M‐ or M‐selective mAChR modulators have been developed that target the topographically distinct allosteric sites. Herein we report the synthesis and preliminary evaluation of C‐labeled positron emission tomography (PET) ligands based on a validated MR positive allosteric modulator VU0467485 (AZ13713945) to facilitate drug discovery. [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). In vitro autoradiography studies indicated that these three ligands possess moderate‐to‐high in vitro specific binding to MR. Nevertheless, further physiochemical property optimization is necessary to overcome the challenges associated with limited brain permeability. : A validated MR positive allosteric modulator VU0467485 (AZ13713945) was evaluated as a preclinical candidate. A series of C‐labeled positron emission tomography (PET) ligands based on VU0467485 were synthesized and preliminarily evaluated. In vitro autoradiography studies indicated that these PET ligands possess moderate‐to‐high in vitro specific binding to MR. Nevertheless, further optimization is necessary to improve brain permeability.
language: eng
source:
identifier: E-ISSN: 1860-7187 ; DOI: 10.1002/cmdc.201800710
fulltext: fulltext
issn:
  • 18607187
  • 1860-7187
url: Link


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titleSynthesis and Preliminary Evaluation of 11 C-Labeled VU0467485/AZ13713945 and Its Analogues for Imaging Muscarinic Acetylcholine Receptor Subtype 4.
creatorDeng, 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, Ming-Rong ; Liang, Steven
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ispartofChemMedChem, February 5, 2019, Vol.14(3), pp.303-309
identifierE-ISSN: 1860-7187 ; DOI: 10.1002/cmdc.201800710
subjectAnimals–Diagnostic Imaging ; Brain–Chemical Synthesis ; Carbon Radioisotopes–Chemistry ; Ligands–Pharmacology ; Molecular Structure–Chemical Synthesis ; Muscarinic Agonists–Chemistry ; Positron-Emission Tomography–Pharmacology ; Pyridazines–Agonists ; Rats–Analysis ; Receptor, Muscarinic M4–Analysis ; Carbon Radioisotopes ; Carbon-11 ; Ligands ; Muscarinic Agonists ; Pyridazines ; Receptor, Muscarinic M4 ; Vu0467485 ; Vu0467485/Az13713945 ; Carbon-11 ; Muscarinic Acetylcholine Receptor Subtype 4
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descriptionMuscarinic acetylcholine receptors (mAChRs) have five distinct subunits (M–M) 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/M‐preferring agonist, in patients of schizophrenia and Alzheimer's disease, M‐ or M‐selective mAChR modulators have been developed that target the topographically distinct allosteric sites. Herein we report the synthesis and preliminary evaluation of C‐labeled positron emission tomography (PET) ligands based on a validated MR positive allosteric modulator VU0467485 (AZ13713945) to facilitate drug discovery. [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). In vitro autoradiography studies indicated that these three ligands possess moderate‐to‐high in vitro specific binding to MR. Nevertheless, further physiochemical property optimization is necessary to overcome the challenges associated with limited brain permeability. : A validated MR positive allosteric modulator VU0467485 (AZ13713945) was evaluated as a preclinical candidate. A series of C‐labeled positron emission tomography (PET) ligands based on VU0467485 were synthesized and preliminarily evaluated. In vitro autoradiography studies indicated that these PET ligands possess moderate‐to‐high in vitro specific binding to MR. Nevertheless, further optimization is necessary to improve brain permeability.
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titleSynthesis and Preliminary Evaluation of 11 C-Labeled VU0467485/AZ13713945 and Its Analogues for Imaging Muscarinic Acetylcholine Receptor Subtype 4.
authorDeng, 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, Ming-Rong ; Liang, Steven
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