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

作者：Mengxin Xu, Hanbo Song, Jie Cai, Junyi Chen, Changlun Wang, Rui Wang, Yü Liu, Xi‐Yang Cui, Jin Du, Zhu Li, Zhibo Liu · 发表于：Journal of Medicinal Chemistry · 年份：2025 · DOI：10.1021/acs.jmedchem.5c00837 · 被引用次数：7 · 研究领域：Peptidase Inhibition and Analysis、Radiopharmaceutical Chemistry and Applications、Medical Imaging Techniques and Applications

Rhenium-188 ( 188 Re) 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 99m Tc with 188 Re is hindered by ReO 4 – ’s lower reducibility. In this study, we designed, synthesized, and systematically evaluated four triamidomonothiol (N 3 S) tetradentate donor type related radiotracers: 188 Re-labeled MAS 3 -FAPI, MAS 3 -DOTA-FAPI, MAE 3 -FAPI, and MAE 3 -DOTA-FAPI. All the radiotracers exhibited efficient radiolabeling with yields exceeding 80%. MAE 3 -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 (MAS 3 -DOTA-FAPI and MAE 3 -DOTA-FAPI) showed enhanced tumor uptake and prolonged retention with significantly reduced hepatic/intestinal accumulation. Notably, [ 188 Re]Re-MAE 3 -DOTA-FAPI achieved high tumor specificity, sustained intralesional retention, and potent therapeutic efficacy, underscoring strong potential for clinical translation.