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

Abstract

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.