Development of ibuprofen-modified fibroblast activation protein radioligands to improve cancer therapy

FAP-targeting radioligands are used in cancer diagnosis and therapy, but their effectiveness is limited by poor tumor uptake and retention. This study aimed to develop new radioligands using an optimized amino acid linker and ibuprofen for better pharmacokinetics. Three novel quinoline-based FAP ligands with an ibuprofen moiety were synthesized and radiolabeled with gallium-68 and lutetium-177. The synthesized FAP ligands FAPI-Ibu1, 2, 3 showed high binding affinity for FAP, with IC₅₀ values of 1.17 ± 0.09, 0.29 ± 0.06, and 0.78 ± 0.12 nM, respectively. ¹⁷⁷Lu-labeled FAP ligands showed stability in vitro and demonstrated significant binding to human plasma proteins as well as FAP specificity. PET imaging and biodistribution studies of ⁶⁸Ga- or ¹⁷⁷Lu-labeled FAPI-Ibu1, 2, 3 revealed improved tumor accumulation and retention. Dosimetry calculation showed that [¹⁷⁷Lu]Lu-FAPI-Ibu3 delivered a 9.9-fold higher absorbed dose to tumor than [¹⁷⁷Lu]Lu-FAPI-04, but only 2.6-fold higher absorbed dose to kidneys leading to 3.8-fold improvement in the tumor-to-kidney absorbed dose ratios. In the endoradiotherapy study, 18.5 MBq of [¹⁷⁷Lu]Lu-FAPI-Ibu3 resulted in longer median survival than the equivalent dose of [¹⁷⁷Lu]Lu-FAPI-04 (22 vs 16 days). Three ibuprofen-modified FAP radioligands significantly improved tumor uptake, retention, and growth suppression compared to [¹⁷⁷Lu]Lu-FAPI-04, with [¹⁷⁷Lu]Lu-FAPI-Ibu3 emerging as the most promising candidate for further clinical translational studies.