含氟磺酰基的靶向PD-L1小分子PET探针的合成及其初步生物学评价  

Synthesis and Preliminary Biological Assessment of Fluorosulfonyl-containing Small-molecular PET Probe Targeting PD-L1

作　　者：胡鑫 张楠 朱君翊 林建国 吕高超[1,2] HU Xin;ZHANG Nan;ZHU Junyi;LIN Jianguo;LV Gaochao(School of Pharmacy,Nanjing Medical University,Nanjing 211166,China;Jiangsu Key Laboratory of Molecular Nuclear Medicine,NHC Key Laboratory of Nuclear Medicine,Jiangsu Institute of Nuclear Medicine,Wuxi 214063,China)

机构地区：[1]南京医科大学药学院,江苏南京211166 [2]江苏省原子医学研究所国家卫生健康委员会核医学重点实验室,江苏省分子核医学重点实验室,江苏无锡214063

出　　处：《合成化学》2024年第7期627-633,共7页Chinese Journal of Synthetic Chemistry

基　　金：国家自然科学基金资助项目(81972906);江苏省自然科学基金资助项目(BK20201134);江苏省333资助项目(2022-33)。

摘　　要：大量研究数据显示,抗肿瘤免疫治疗的效果与肿瘤中细胞程序性死亡配体1(PD-L1)的表达水平呈正相关。使用放射性核素标记的探针进行正电子发射计算机断层扫描(PET)成像可以准确定量患者全身PD-L1表达水平的动态变化。以联苯类PD-L1小分子抑制剂的母核为结构基础进行优化,并引入氟磺酰基,成功合成靶向PD-L1的小分子化合物8。通过质谱、核磁(^(1)H/^(13)C/^(19)F NMR)表征验证了化合物8的结构正确,并利用均相时间分辨荧光(TR-FRET)测得其抑制PD-1/PD-L1结合的IC_(50)值为237.2±9.37 nM。体外细胞毒性实验表明:化合物8具有良好的生物相容性。通过“^(18)F-^(19)F”一步法标记合成小分子PET探针[^(18)F]8,放射转化产率达79%,放射化学纯度大于98%,在PBS和小鼠血清中均保持高度稳定,脂水分配系数为1.87±0.19。探针[^(18)F]8在小鼠黑色素瘤B16-F10细胞中的最大摄取值达到2.23±0.05%AD,且可被化合物8显著阻断(0.24±0.21%AD)。因此,简单、快速、高产的标记方法和对PD-L1良好的亲和力为探针[^(18)F]8的PET显像提供了基础。A number of research data have demonstrated that the effect of anti-tumor immunotherapy is positively correlated with the expression level of programmed cell death protein ligand 1(PD-L1)in tumors.Positron emission computed tomography(PET)imaging using radionuclide-labeled probes is able to precisely determine the level of PD-L1 expression in vivo.Here,a novel small-molecule compound 8 targeting PD-L1 was synthesized by introducing fluorosulfonyl group into the scaffold of biphenyl small-molecule inhibitor.The structure of compound 8 was characterized by MS and ^(1)H/^(13)C/^(19)F NMR characterization.Compound 8 showed good inhibit activity to the interaction of PD-1/PD-L1 with IC_(50) values of 237.2±9.37 nM measured by homogeneous time-resolved fluorescence.In vivo experiments showed that compound 8 had good biocompatibility.Small-molecule PET probe[^(18)F]8 was synthesized by“^(18)F-^(19)F”ion exchange of fluorosulfonyl group in over 79% radio-conversion and nearly 98% radio-chemical yield with high stabilitye in both PBS and mouse serum.For[^(18)F]8,the lipid-water partition coefficient was 1.87±0.19.The maximum uptake of probe[^(18)F]8 reached 2.23±0.05% AD in mouse melanoma cells B16-F10 and the uptake could be significantly blocked by compound 8(0.24±0.21%AD).Thus,the simple,rapid,high-yield labeling method and good affinity for PD-L1 provide the basis for PET imaging of probe[^(18)F]8.

关 键 词：PD-L1 氟磺酰基 小分子PET探针 亲和力 ^(18)F-^(19)F 

分 类 号：R730.44[医药卫生—肿瘤]