State Key Laboratory of Vaccines for Infectious Diseases, Center for Molecular Imaging and Translational Medicine, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, 4221-116 Xiang'An South Rd, Xiamen 361102, China.
Theranostics and Translational Research Center, Institute of Clinical Medicine, Department of Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 1 Shuaifuyuan, Dongcheng District, Beijing 100730, China.
J Med Chem. 2024 May 23;67(10):8361-8371. doi: 10.1021/acs.jmedchem.4c00544. Epub 2024 May 10.
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 F-labeled biotin/FAPI-conjugated heterobivalent radioligands ([F]AlF-NSFB, [F]AlF-NSFBP, and [F]AlF-NSFBP), synergistically targeting both fibroblast activation protein (FAP) and biotin receptor (BR), to enhance specific tumor uptake and retention. The and 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 [F]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 [F]AlF-NSFBP holds significant promise as a candidate for further clinical translational studies.
由于不同癌症类型的复杂异质性，杂二聚体策略已被广泛应用于提高肿瘤诊断的效果。在本研究中，我们开发了一系列新型 F 标记的生物素/FAPI 偶联的杂双价放射性配体([F]AlF-NSFB、[F]AlF-NSFBP 和 [F]AlF-NSFBP)，协同靶向成纤维细胞激活蛋白(FAP)和生物素受体(BR)，以增强肿瘤的特异性摄取和滞留。评估了这些双靶向示踪剂的 和 生物学特性，特别关注在 A549 和 HT1080-FAP 荷瘤小鼠中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[F]AlF-NSF 相比，生物素/FAPI 偶联的杂二聚体在肿瘤中表现出高摄取和延长的保留。总之，作为概念验证研究，这些发现验证了生物素/FAPI 偶联的杂二聚体的优越性，以及生物素和连接子对放射性配体药代动力学的积极影响。在它们之中，双特异性[F]AlF-NSFBP 作为进一步临床转化研究的候选物具有重要意义。
