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

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Acta Pharmaceutica Sinica B 2023年第1期13卷 213-226页

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 Department of Radiology Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital and Harvard Medical SchoolBostonMA 02114USA Department of Nuclear Medicine Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Drug Discovery Biology Monash Institute of Pharmaceutical SciencesMonash UniversityParkvilleVIC 3052Australia Neuromedicines Discovery Centre Monash Institute of Pharmaceutical SciencesMonash UniversityParkvilleVIC 3052Australia Hubei Collaborative Innovation Centre for Non-power Nuclear Technology College of Nuclear Technology&Chemistry and BiologyHubei University of Science and TechnologyXianning 437100China Department of Neurology Massachusetts General HospitalHarvard Medical SchoolBostonMA 02114USA Department of Physiology and Pharmacology Wake Forest School of MedicineWinston SalemNC 27157USA Terasaki Institute for Biomedical Innovation(TIBI) Los AngelesCA 90024USA Center of Cyclotron and PeT Radiopharmaceuticals Department of Nuclear Medicine and PET/CT-MRI Centerthe First Affiliated Hospital of Jinan UniversityGuangzhou 510630China

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 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 ***,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 ***,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.

关键词： Muscarinicacetylcholine receptor Positronemission tomography Neuroimaging Neuropharmacology Neurological disorders

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Aging and menopause reprogram osteoclast precursors for aggressive bone resorption

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Bone Research 2020年第3期8卷 333-342页

作者： Anais Marie Julie Moller Jean-Marie Delaisse Jacob Bastholm Olesen Jonna Skov Madsen Luisa Matos Canto troels Bechmann Silvia Regina Rogatto Kent Soe Clinical Cell Biology Lillebaelt HospitalUniversity Hospital of Southern Denmark7100 VejleDenmark Department of Regional Health Research University of Southern Denmark5230 Odense MDenmark Department of Clinical Biochemistry and Immunology Lillebaelt HospitalUniversity Hospital of Southern Denmark7100 VejleDenmark Clinical Cell Biology Department of PathologyOdense University Hospital5000 Odense CDenmark Department of Clinical Research University of Southern Denmark5230 Odense MDenmark Department of Molecular Medicine University of Southern Denmark5230 Odense MDenmark Department of Clinical Genetics Lillebaelt HospitalUniversity Hospital of Southern Denmark7100 VejleDenmark Department of Oncology Lillebaelt HospitalUniversity Hospital of Southern Denmark7100 VejleDenmark OPeN Odense Patient data Explorative NetworkOdense University Hospital5000 Odense CDenmark

Women gradually lose bone from the age of〜35 years,but around menopause,the rate of bone loss escalates due to increasing bone resorption and decreasing bone formation levels,rendering these individuals more prone to developing *** increased osteoclast activity has been linked to a reduced estrogen level and other hormonal ***,it is unclear whether intrinsic changes in osteoclast precursors around menopause can also explain the increased osteoclast ***,we set up a protocol in which CD14f blood monocytes were isolated from 49 female donors(40-66 years old).Cells were differentiated into osteoclasts,and data on differentiation and resorption activity were *** multiple linear regression analyses combining in vitro and in vivo data,we found the following:(1)age and menopausal status correlate with aggressive osteoclastic bone resorption in vitro;(2)the type I procollagen N-terminal propeptide level in vivo inversely correlates with osteoclast resorption activity in vitro;(3)the protein level of mature cathepsin K in osteoclasts in vitro increases with age and menopause;and(4)the promoter of the gene encoding the dendritic cell-specific transmembrane protein is less methylated with *** conclude that monocytes are"reprogrammed"in vivo,allowing them to"remember"age,the menopausal status,and the bone formation status in vitro,resulting in more aggressive *** discovery suggests that this may be mediated through DNA *** suggest that this may have clinical implications and could contribute to understanding individual differences in age-and menopause-induced bone loss.

关键词： osteoclast menopause osteoporosis

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向日常生活致敬:2018 danishdesign MAKeRS家具展

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现代装饰 2018年第12期 86-93页

作者： Alvilde Holm Antonio Scaffidi edvard & Steenfatt ellinor ericsson evalou Hauge Gustav Max Lindholm Jesper Junge Jonas Lyndby Jensen Nordvink/Anne N?rbjerg & Sanne Kyed ?rn Duvald Petter Th?rne Rasmus Warberg Rikke Frost Sahtel Mouritsen Lystager Signe?.Lund & Isabel Ahm Thomas Albertsen Thomas e.Alken troels Flensted Witek Golik danishdesign MAKeRS Kristine Funch & emilia Therese 彭佳 Studio Fem-Anders engholm & Sarah Cramer

本届2018danishdesign MAKeRS家具展的主题为“向日常生活致敬”,其灵感来源于丹麦诗人Dan Turell诗歌中关于日常生活之美的语句,同时也表达了对于如今设计行业中奢侈浪费现象的思考。

关键词：家具展浪费现象设计行业 Dan

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