Duan Xiaojiang, Zhang Zhuochen, Xu Hongchuang, Zhang Jingming, Yan Yue, Yang Xing
Department of Nuclear Medicine, Peking University First Hospital, Beijing 100034, China.
Department of Nuclear Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China.
Mol Pharm. 2025 Jan 6;22(1):221-228. doi: 10.1021/acs.molpharmaceut.4c00858. Epub 2024 Dec 9.
Precisely assessing nectin-4 expression in tumors is important in identifying patients who may benefit from nectin-4-targeted therapies. In our previous work, we developed a bicyclic peptide-based nectin-4-targeting radiotracer Ga-N188 and validated its nectin-4 detection efficacy. However, the relatively short half-life and low positron emission rate of Ga limit its further application. In this study, we constructed three novel nectin-4-targeting ligands N230-232 based on a bicyclic peptide structure and labeled with radionuclide F, which has a longer half-life and a higher positron emission rate, for PET imaging. Micro-PET/CT imaging-based screening showed that AlF-N231 had the best imaging contrast with a tumor-to-muscle ratio of 10.97 ± 2.39. Further characterization demonstrated that ligand N231 had a high affinity to nectin-4 with a of 4.29 nM, and AlF-N231 had a good stability and safety profile . Biodistribution studies validated the specific binding of AlF-N231 to nectin-4 , with tumor uptake in the nectin-4 SW780 tumor group being 1.45- and 3.75-fold higher than that in the nectin-4 5637 tumor group and blocking group, respectively. Based on the results of this work, AlF-N231 has promising capability for noninvasive nectin-4 detection .
精确评估肿瘤中NECTIN-4的表达对于识别可能从NECTIN-4靶向治疗中获益的患者至关重要。在我们之前的工作中，我们开发了一种基于双环肽的NECTIN-4靶向放射性示踪剂Ga-N188，并验证了其NECTIN-4检测效能。然而，Ga相对较短的半衰期和较低的正电子发射率限制了其进一步应用。在本研究中，我们基于双环肽结构构建了三种新型的NECTIN-4靶向配体N230-232，并用半衰期更长、正电子发射率更高的放射性核素F进行标记，用于PET成像。基于微型PET/CT成像的筛选显示，AlF-N231具有最佳的成像对比度，肿瘤与肌肉的比值为10.97±2.39。进一步的表征表明，配体N231对NECTIN-4具有高亲和力，解离常数为4.29 nM，并且AlF-N231具有良好的稳定性和安全性。生物分布研究验证了AlF-N231与NECTIN-4的特异性结合，在NECTIN-4 SW780肿瘤组中的肿瘤摄取分别比NECTIN-4 5637肿瘤组和阻断组高1.45倍和3.75倍。基于这项工作的结果，AlF-N231具有用于无创检测NECTIN-4的良好潜力。
