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

作     者：Ahmed Haider Xiaoyun Deng Olivia Mastromihalis Stefanie K.Pfister Troels E.Jeppesen Zhiwei Xiao Vi Pham Shaofa Sun Jian Rong Chunyu Zhao Jiahui Chen Yinlong Li Theresa R.Connors April T.Davenport James B.Daunais Vahid Hosseini Wenqing Ran Arthur Christopoulos Lu Wang Celine Valant Steven H.Liang 

作者机构：Department of RadiologyDivision of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital and Harvard Medical SchoolBostonMA 02114USA Department of Nuclear MedicineTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Drug Discovery BiologyMonash Institute of Pharmaceutical SciencesMonash UniversityParkvilleVIC 3052Australia Neuromedicines Discovery CentreMonash Institute of Pharmaceutical SciencesMonash UniversityParkvilleVIC 3052Australia Hubei Collaborative Innovation Centre for Non-power Nuclear TechnologyCollege of Nuclear Technology&Chemistry and BiologyHubei University of Science and TechnologyXianning 437100China Department of NeurologyMassachusetts General HospitalHarvard Medical SchoolBostonMA 02114USA Department of Physiology and PharmacologyWake Forest School of MedicineWinston SalemNC 27157USA Terasaki Institute for Biomedical Innovation(TIBI)Los AngelesCA 90024USA Center of Cyclotron and PET RadiopharmaceuticalsDepartment of Nuclear Medicine and PET/CT-MRI Centerthe First Affiliated Hospital of Jinan UniversityGuangzhou 510630China 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2023年第13卷第1期

页      面：213-226页

核心收录：

学科分类：081704[工学-应用化学] 1001[医学-基础医学(可授医学、理学学位)] 07[理学] 070304[理学-物理化学(含∶化学物理)] 08[工学] 0817[工学-化学工程与技术] 0703[理学-化学] 10[医学] 

基　　金：supported by the Swiss National Science Foundation(SNSF) supported by the National Health and Medical Research Council(NHMRC)Program Grant(APP1055134,USA) the Australian Research Council(ARC)Discovery Project(DP190102950,USA) supported by grants from Fulbright Denmark,The Lundbeck Foundation,Eva and Henry Frònkels foundation,The Danish Cancer Society,The Harboe Foundation 

主　　题：Muscarinicacetylcholine receptor Positronemission tomography Neuroimaging Neuropharmacology Neurological disorders 

摘      要：There is an accumulating body of evidence implicating the muscarinic acetylcholine receptor4(M4)in schizophrenia and dementia with Lewy bodies,however,a clinically validated M4positron emission tomography(PET)radioligand is currently *** such,the aim of this study was to develop a suitable M4PET ligand that allows the non-invasive visualization of M4in the ***-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 purity99%.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 ***,in the presence of carbachol,a significant increase in tracer binding was observed in the rat striatum,which was reduced by60%under blocking conditions,thus indicating that orthosteric ligand interaction is required for efficient binding o f[18F]12 to the allosteric ***,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 *** 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 *** conclusion,we report on the identification and preclinical development of the first radiofluorinated M4PET radioligand with promising *** availability of a clinically validated M4PET radioligand harbors potential to facilitate drug development and provide a useful diagnostic tool for non-invasive imaging.