Ruan Qing, Diao Lina, Li Zuojie, Ding Dajie, Han Peiwen, Jiang Yuhao, Yin Guangxing, Feng Junhong, Wang Qianna, Jiang Jianyong, Zhang Junbo
Key Laboratory of Radiopharmaceuticals of the Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), College of Chemistry, Beijing Normal University, Beijing, 100875, PR China; Key Laboratory of Beam Technology of the Ministry of Education, School of Physics and Astronomy, Beijing Normal University, Beijing, 100875, PR China.
Key Laboratory of Radiopharmaceuticals of the Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), College of Chemistry, Beijing Normal University, Beijing, 100875, PR China.
Eur J Med Chem. 2025 Apr 5;287:117343. doi: 10.1016/j.ejmech.2025.117343. Epub 2025 Jan 30.
Fibroblast activation protein (FAP) is a crucial target for tumor diagnosis and treatment. FAP inhibitors (FAPIs) can selectively bind to FAP, and ligands with multiple targeting groups are anticipated to improve tumor-specific uptake. A dimeric FAPI ligand (L2) with high affinity for FAP was selected. Four hydrophilic Tc-labeled complexes ([Tc]Tc-L2-TPPTS, [Tc]Tc-L2-TPPMS, [Tc]Tc-L2-PDA, and [Tc]Tc-L2-NIC) were successfully prepared and exhibited good stability in vitro. Among them, [Tc]Tc-L2-TPPTS and [Tc]Tc-L2-PDA showed superior cellular uptake and specific binding to FAP. They displayed minimal nontarget uptake in normal mice and exhibited significant tumor uptake (22.01 ± 1.38 % ID/g and 26.58 ± 2.17 % ID/g at 1 h post-injection) with high specificity for FAP in U87MG tumor-bearing mice. SPECT/CT imaging experiments revealed specific accumulation of both complexes at the U87MG, PANC-1, and HT-1080-FAP tumor sites, suggesting their excellent specificity for FAP. In particular, [Tc]Tc-L2-TPPTS has lower nontarget uptake in various tumor models and accelerated blood clearance. Additionally, an L2-TPPTS kit was successfully prepared providing convenient conditions for subsequent clinical transformation research.
成纤维细胞活化蛋白（FAP）是肿瘤诊断和治疗的关键靶点。FAP抑制剂（FAPIs）可选择性结合FAP，预期具有多个靶向基团的配体可提高肿瘤特异性摄取。筛选出一种对FAP具有高亲和力的二聚体FAPI配体（L2）。成功制备了四种亲水性锝标记配合物（[Tc]Tc-L2-TPPTS、[Tc]Tc-L2-TPPMS、[Tc]Tc-L2-PDA和[Tc]Tc-L2-NIC），并在体外表现出良好的稳定性。其中，[Tc]Tc-L2-TPPTS和[Tc]Tc-L2-PDA表现出卓越的细胞摄取和对FAP的特异性结合。它们在正常小鼠中显示出最小的非靶向摄取，并在接种U87MG肿瘤的小鼠中表现出显著的肿瘤摄取（注射后1小时为22.01±1.38% ID/g和26.58±2.17% ID/g），对FAP具有高度特异性。SPECT/CT成像实验显示这两种配合物在U87MG、PANC-1和HT-1080-FAP肿瘤部位均有特异性积聚，表明它们对FAP具有出色的特异性。特别是，[Tc]Tc-L2-TPPTS在各种肿瘤模型中的非靶向摄取较低，且血液清除加快。此外，成功制备了L2-TPPTS试剂盒，为后续临床转化研究提供了便利条件。
