Design, Synthesis, and Evaluation of OncoFAP Derivatives with the Albumin Binder as Novel Antitumor Radiopharmaceuticals.

Fibroblast activation protein (FAP), a type II transmembrane serine protease, is selectively and highly expressed on the membranes of cancer-associated fibroblasts within the stroma of various epithelial-derived malignancies. In recent years, numerous quinoline-based small organic radioligands targeting FAP, such as OncoFAP, have been developed and clinically utilized for the diagnosis of both primary and metastatic tumors. However, despite their selective accumulation, conventional FAP ligands often suffer from a relatively short half-life in tumors, limiting their efficacy in radionuclide therapy. In this study, we leveraged the structure of UAMC-1110, which was known for its high affinity for FAP, and modified it by adding functional chemical groups (unnatural amino acid, linkers, and albumin binders) to improve its pharmacokinetic and pharmacodynamic properties, thereby enhancing tumor targeting and prolonging tumor retention. Among the synthesized derivatives, XH03-11 emerged as a standout candidate due to its excellent in vitro characteristics, superior in vivo biodistribution profile, and demonstrated therapeutic efficacy in tumor-bearing mice.