【摘要】 本研究以4-喹啉基-甘氨基-2-氰基吡咯烷为骨架，对连接基团进行碳链延长及羟基修饰成功合成FAPI衍生物ATE-FAPI-03；通过亲电取代反应实现其¹³¹I标记，并对标记化合物¹³¹I-FAPI-03的脂水分配比、体外稳定性等进行分析；开展细胞结合、内吞、流出等实验以评价¹³¹I-FAPI-03的体外动力学特征；并考察了¹³¹I-FAPI-03在荷胶质瘤小鼠体内的分布情况。结果表明：¹³¹I-FAPI-03为亲脂性小分子，并具有良好的体外稳定性；与FAPα阳性细胞U87MG孵育10 min时的结合率为（22.00±0.35）%，且随着孵育时间的延长结合率有明显的上升趋势，而与FAPα阴性细胞MCF-7的结合率始终处于较低水平；通过竞争结合实验测得¹³¹I-FAPI-03的IC50值为45.5 nM，表明其对FAPα具有较高的亲和力；大部分与U87MG细胞结合的¹³¹I-FAPI-03可被细胞内吞，但其在细胞中的滞留能力偏低。¹³¹I-FAPI-03在荷胶质瘤小鼠体内具有快速的肿瘤靶向能力：经尾静脉注射5 min后，肿瘤组织对¹³¹I-FAPI-03的放射性摄取值为（14.90±3.21）%ID/g，注射2 h后，肿瘤/肌肉的放射性摄取比值达到（43.7±16.7）。上述结果为新型FAPα靶向药物的研发提供了重要的参考。更多还原

【Abstract】 Using N-（4-quinolinoyl）-Gly-（2-cyanopyrrolidine） as scaffold, we prolonged the linker with serine to obtain a FAPI derivative ATE-FAPI-03,which was subsequently labeled with ¹³¹I by electrophilic substitution. Then the in vitro stability, Log P value, binding affinity, targeting properties and biodistribution behavior of ¹³¹I-FAPI-03 was evaluated. Results show that ¹³¹I-FAPI-03 was lipophilic and stable in vitro,capable of specifically binding to FAPα-positive U87MG cells fast with a major proportion trapped intracellularly. After 10 min of incubation,¹³¹I-FAPI-03 showed a specific binding rate of（22.00 ± 0.35）%,and the binding rate increased with the incubation time,to a peak of（37.5 ± 0.83）% at 180 min. However,the FAPα-negative MCF-7 cells exhibited very low uptake of ¹³¹I-FAPI-03 at any time point. The IC50 measured by the competition assay indicated significant binding property of ¹³¹I-FAPI-03. Biodistribution studies revealed that ¹³¹I-FAPI-03 could rapidly accumulate in tumor sites with an uptake of（14.90 ± 3.21）% ID/g at 5 min post injection. At2 h post injection,¹³¹I-FAPI-03 displayed the highest tumor-to-muscle ratio of 43.7 ± 16.7. All above results provided important reference for the development of novel FAPα-targeting tracers.更多还原