Discovery of a highly specific ^(18)F-labeled PET ligand for phosphodiesterase 10A enabled by novel spirocyclic iodonium ylide radiofluorination  

作　　者：Zhiwei Xiao Huiyi Wei Yi Xu Ahmed Haider Junjie Wei Shiyu Yuan Jian Rong Chunyu Zhao Guocong Li Weibin Zhang Huangcan Chen Yuefeng Li Lingling Zhang Jiyun Sun Shaojuan Zhang Hai-Bin Luo Sen Yan Qijun Cai Lu Hou Chao Che Steven H.Liang Lu Wang 

机构地区：[1]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 [2]Division of Nuclear Medicine and Molecular Imaging,Massachusetts General Hospital&Department of Radiology,Harvard Medical School,Boston,MA 02114,USA [3]Department of Cardiology,the First Affiliated Hospital of Jinan University,Guangzhou 510630,China [4]State Key Laboratory of Chemical Oncogenomics,Key Laboratory of Chemical Genomics,Peking University Shenzhen Graduate School,Shenzhen 518055,China [5]Guangdong Landau Biotechnology Co.Ltd.,Guangzhou 510555,China [6]Key Laboratory of Tropical Biological Resources of Ministry of Education,School of Pharmaceutical Sciences,Hainan University,Haikou 570228,China [7]Guangdong-Hongkong-Macao Institute of CNS Regeneration,Ministry of Education CNS Regeneration Collaborative Joint Laboratory,Jinan University,Guangzhou 510632,China

出　　处：《Acta Pharmaceutica Sinica B》2022年第4期1963-1975,共13页药学学报（英文版）

基　　金：the support of K.C.Wong Education Foundation (China);financially supported by the National Natural Science Foundation of China (No.82071974);Shenzhen Basic Research Project (JCYJ20180503182116931, China);Guangdong Basic and Applied Basic Research Foundation (2020A1515011192, 2018A0303130052, China);Guangzhou Key Research Program on Brain Science (202007030008, China);the Fundamental Research Funds for the Central Universities (21619104, 21621051, China)

摘　　要：As a member of cyclic nucleotide phosphodiesterase(PDE)enzyme family,PDE10A is in charge of the degradation of cyclic adenosine(cAMP)and guanosine monophosphates(cGMP).While PDE10A is primarily expressed in the medium spiny neurons of the striatum,it has been implicated in a variety of neurological disorders.Indeed,inhibition of PDE10A has proven to be of potential use for the treatment of central nervous system(CNS)pathologies caused by dysfunction of the basal ganglia–of which the striatum constitutes the largest component.A PDE10A-targeted positron emission tomography(PET)radioligand would enable a better assessment of the pathophysiologic role of PDE10A,as well as confirm the relationship between target occupancy and administrated dose of a given drug candidate,thus accelerating the development of effective PDE10A inhibitors.In this study,we designed and synthesized a novel ^(18)F-aryl PDE10A PET radioligand,codenamed[^(18)F]P10A-1910([^(18)F]9),in high radiochemical yield and molar activity via spirocyclic iodonium ylide-mediated radiofluorination.[^(18)F]9 possessed good in vitro binding affinity(IC_(50)=2.1 nmol/L)and selectivity towards PDE10A.Further,[^(18)F]9 exhibited reasonable lipophilicity(logD=3.50)and brain permeability(P_(app)>10×10^(−6) cm/s in MDCK-MDR1 cells).PET imaging studies of[^(18)F]9 revealed high striatal uptake and excellent in vivo specificity with reversible tracer kinetics.Preclinical studies in rodents revealed an improved plasma and brain stability of[^(18)F]9 when compared to the current reference standard for PDE10A-targeted PET,[^(18)F]MNI659.Further,dose–response experiments with a series of escalating doses of PDE10A inhibitor 1 in rhesus monkey brains confirmed the utility of[^(18)F]9 for evaluating target occupancy in vivo in higher species.In conclusion,our results indicated that[^(18)F]9 is a promising PDE10A PET radioligand for clinical translation.

关 键 词：Phosphodiesterase 10A PET radioligand 18F Spirocyclic iodonium ylide Nonhuman primate Target occupancy 

分 类 号：R965[医药卫生—药理学]