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). In vitro studies also confirmed the FAP-specific binding. In vivo 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.