Rational Design and Pharmacomodulation of 18F‑Labeled Biotin/FAPI-Conjugated Heterodimers

• Published in: Journal of medicinal chemistry 2024-05, Vol.67 (10), p.8361-8371
• Main Authors: Chen, Xuedong, Xia, Dongsheng, Zeng, Xueyuan, Meng, Lingxin, Wang, Yanjie, Li, Huifeng, Zhang, Jingru, Zhao, Zuoquan, Zhuang, Rongqiang, Fang, Jianyang, Zhang, Xianzhong, Guo, Zhide
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.4c00544

Due to the complex heterogeneity in different cancer types, the heterodimeric strategy has been intensively practiced to improve the effectiveness of tumor diagnostics. In this study, we developed a series of novel 18F-labeled biotin/FAPI-conjugated heterobivalent radioligands ([18F]­AlF-NSFB, [18F]­AlF-NSFBP2, and [18F]­AlF-NSFBP4), synergistically targeting both fibroblast activation protein (FAP) and biotin receptor (BR), to enhance specific tumor uptake and retention. The in vitro and in vivo biological properties of these dual-targeting tracers were evaluated, with a particular focus on positron emission tomography imaging in A549 and HT1080-FAP tumor-bearing mice. Notably, in comparison to the corresponding FAP-targeted monomer [18F]­AlF-NSF, biotin/FAPI-conjugated heterodimers exhibited a high uptake in tumor and prolong retention. In conclusion, as a proof-of-concept study, the findings validated the superiority of biotin/FAPI-conjugated heterodimers and the positive influence of biotin and linker on pharmacokinetics of radioligands. Within them, the bispecific [18F]­AlF-NSFBP4 holds significant promise as a candidate for further clinical translational studies.