Design, Structure Optimization, and Preclinical Evaluation of ¹⁸⁸Re-Labeled FAPI for Targeted Radionuclide Therapy

Rhenium-188 (¹⁸⁸Re) is a promising theranostic radionuclide due to its cost-effectiveness, therapeutic β^- emissions, and SPECT-compatible γ rays. However, Re's complex coordination chemistry challenges stable bifunctional chelator development. Despite sharing Group 7 traits with technetium, substituting ^99mTc with ¹⁸⁸Re is hindered by ReO₄^-'s lower reducibility. In this study, we designed, synthesized, and systematically evaluated four triamidomonothiol (N₃S) tetradentate donor type related radiotracers: ¹⁸⁸Re-labeled MAS₃-FAPI, MAS₃-DOTA-FAPI, MAE₃-FAPI, and MAE₃-DOTA-FAPI. All the radiotracers exhibited efficient radiolabeling with yields exceeding 80%. MAE₃-based chelators demonstrated good stability (RCP >90% at 6 h). <i>In vitro</i> studies also confirmed the FAP-specific binding. <i>In vivo</i> performance through SPECT/CT imaging and biodistribution studies in HT1080-FAP xenografts revealed distinct pharmacokinetic profiles: DOTA-modified tracers (MAS₃-DOTA-FAPI and MAE₃-DOTA-FAPI) showed enhanced tumor uptake and prolonged retention with significantly reduced hepatic/intestinal accumulation. Notably, [¹⁸⁸Re]Re-MAE₃-DOTA-FAPI achieved high tumor specificity, sustained intralesional retention, and potent therapeutic efficacy, underscoring strong potential for clinical translation.