Design and Biological Evaluation of FAP-Man, a Mannosylated FAP-Targeted Radioglycopeptide for Tumor Imaging and Radionuclide Therapy

Abstract Fibroblast activation protein (FAP) is an attractive target for radiotheranostic development because of its abundant expression in tumor-associated fibroblasts and limited distribution in normal tissues. Here, we developed FAP-Man, a mannosylated FAP-targeted radioglycopeptide based on the FAP-2286 scaffold, to optimize tumor targeting and pharmacokinetic properties. Compared with [68Ga]Ga-FAP-2286, [68Ga]Ga-FAP-Man showed higher tumor uptake in U87MG tumor-bearing mice (16.917 ± 4.986 vs 3.188 ± 0.535 %ID/g at 1 h post-injection) and improved tumor-to-liver contrast. Both [177Lu]Lu-FAP-Man and [225Ac]Ac-FAP-Man significantly inhibited tumor growth compared with PBS-treated controls. Preliminary clinical PET imaging further supported its potential for favorable lesion visualization and lesion-to-background contrast, particularly for hepatic lesions. These findings support further evaluation of FAP-Man as a FAP-targeted radiopharmaceutical candidate.