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.

中文翻译：

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18F标记生物素/FAPI缀合异二聚体的合理设计和药物调节


由于不同癌症类型的复杂异质性，异二聚体策略已被广泛实践以提高肿瘤诊断的有效性。在这项研究中，我们开发了一系列新型 ¹⁸ F标记的生物素/FAPI缀合的异二价放射性配体（[ ¹⁸ F]AlF-NSFB，[ ¹⁸ F]AlF-NSFBP ₂ 和 [ ¹⁸ F]AlF-NSFBP ₄ )，协同靶向成纤维细胞激活蛋白 (FAP) 和生物素受体 (BR ），以增强特定肿瘤的摄取和保留。对这些双靶向示踪剂的体外和体内生物学特性进行了评估，特别关注 A549 和 HT1080-FAP 荷瘤小鼠的正电子发射断层扫描成像。值得注意的是，与相应的 FAP 靶向单体 [ ¹⁸ F]AlF-NSF 相比，生物素/FAPI 缀合的异二聚体在肿瘤中表现出高摄取率并延长保留时间。总之，作为一项概念验证研究，研究结果验证了生物素/FAPI 缀合异二聚体的优越性以及生物素和接头对放射性配体药代动力学的积极影响。其中，双特异性 [ ¹⁸ F]AlF-NSFBP ₄ 作为进一步临床转化研究的候选者具有重要前景。