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Structure-activity relationship of pyrazol-4-yl-pyridine derivatives and identification of a radiofluorinated probe for imaging the muscarinic acetylcholine receptor M4

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收录情况： ◇ SCIE ◇ 统计源期刊 ◇ CSCD-C ◇ 卓越：领军期刊

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单位： [1]Department of Radiology, Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. [2]Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. [3]Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia. [4]Neuromedicines Discovery Centre, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia. [5]Hubei Collaborative Innovation Centre for Non-power Nuclear Technology, College of Nuclear Technology & Chemistry and Biology, Hubei University of Science and Technology, Xianning 437100, China. [6]Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. [7]Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston Salem, NC 27157, USA. [8]Terasaki Institute for Biomedical Innovation (TIBI), Los Angeles, CA 90024, USA. [9]Center of Cyclotron and PET Radiopharmaceuticals, Department of Nuclear Medicine and PET/CT-MRI Center, the First Affiliated Hospital of Jinan University, Guangzhou 510630, China.

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关键词： Muscarinic acetylcholine receptor Positron emission tomography Neuroimaging Neuropharmacology Neurological disorders

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There is an accumulating body of evidence implicating the muscarinic acetylcholine receptor 4 (M4) in schizophrenia and dementia with Lewy bodies, however, a clinically validated M4 positron emission tomography (PET) radioligand is currently lacking. As such, the aim of this study was to develop a suitable M4 PET ligand that allows the non-invasive visualization of M4 in the brain. Structure-activity relationship studies of pyrazol-4-yl-pyridine derivates led to the discovery of target compound 12 - a subtype-selective positive allosteric modulator (PAM). The radiofluorinated analogue, [18F]12, was synthesized in 28 ± 10% radiochemical yield, >37 GBq/μmol and an excellent radiochemical purity >99%. Initial in vitro autoradiograms on rodent brain sections were performed in the absence of carbachol and showed moderate specificity as well as a low selectivity of [18F]12 for the M4-rich striatum. However, in the presence of carbachol, a significant increase in tracer binding was observed in the rat striatum, which was reduced by >60% under blocking conditions, thus indicating that orthosteric ligand interaction is required for efficient binding of [18F]12 to the allosteric site. Remarkably, however, the presence of carbachol was not required for high specific binding in the non-human primate (NHP) and human striatum, and did not further improve the specificity and selectivity of [18F]12 in higher species. These results pointed towards significant species-differences and paved the way for a preliminary PET study in NHP, where peak brain uptake of [18F]12 was found in the putamen and temporal cortex. In conclusion, we report on the identification and preclinical development of the first radiofluorinated M4 PET radioligand with promising attributes. The availability of a clinically validated M4 PET radioligand harbors potential to facilitate drug development and provide a useful diagnostic tool for non-invasive imaging.© 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.

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出版当年[2022]版：

大类 | 1 区

化学

小类 | 1 区药学

最新[2025]版：

大类 | 1 区

医学

小类 | 1 区药学

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出版当年[2021]版：

Q1 PHARMACOLOGY & PHARMACY

最新[2023]版：

Q1 PHARMACOLOGY & PHARMACY

影响因子： 14.8 最新[2023版] 14.1 最新五年平均 14.907 出版当年[2021版] 12.903 出版当年五年平均 11.614 出版前一年[2020版] 14.5 出版后一年[2022版]

第一作者：

第一作者单位： [1]Department of Radiology, Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

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通讯机构： [3]Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia. [4]Neuromedicines Discovery Centre, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.

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Structure-activity relationship of pyrazol-4-yl-pyridine derivatives and identification of a radiofluorinated probe for imaging the muscarinic acetylcholine receptor M4

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