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 

机构地区：[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

出　　处：《Acta Pharmaceutica Sinica B》2023年第1期213-226,共14页药学学报（英文版）

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。

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 lacking.As such,the aim of this study was to develop a suitable M4PET ligand that allows the non-invasive visualization of M4in 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 o f[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 M4PET radioligand with promising attributes.The availability of a clinically validated M4PET radioligand harbors potential to facilitate drug development and provide a useful diagnostic tool for non-invasive imaging.

关 键 词：Muscarinicacetylcholine receptor Positronemission tomography NEUROIMAGING NEUROPHARMACOLOGY Neurological disorders 

分 类 号：R313[医药卫生—基础医学] O641.4[理学—物理化学]