Development of Glycosylated and Dimeric FAP-Targeted Radiotracers for Preclinical Evaluation in FAP-Positive Glioblastoma Models.

Fibroblast activation protein (FAP) is an important target for tumor diagnosis and therapy. In this study, two FAP-targeted radioligands, the monomeric [68Ga]Ga-DOTA-T1-FAPI and the dimeric [68Ga]Ga-DOTA-T1-(FAPI)2, were designed by introducing a glucose linker into FAPI-04 and its dimer, and their FAP-targeting capability was further evaluated. In vitro studies demonstrated that [68Ga]Ga-DOTA-T1-(FAPI)2 exhibited specific uptake in FAP-positive U87 MG cells. Small animal positron emission tomography and computed tomography (PET/CT) imaging and biodistribution studies showed that the dimeric tracer exhibited higher tumor uptake (9.5 ± 1.75% ID/g at 30 min) and superior tumor-to-nontarget ratios compared with [68Ga]Ga-DOTA-T1-FAPI (3.02 ± 0.19% ID/g at 30 min) and [68Ga]Ga-DOTA-FAPI-04 (1.44 ± 0.34% ID/g at 30 min). Furthermore, [177Lu]Lu-DOTA-T1-(FAPI)2 displayed high tumor uptake (10.83 ± 1.92% ID/g at 4 h) and favorable imaging contrast. Overall, the combination of glycosylation and dimerization provides a promising strategy for developing efficient FAP-targeted diagnostic and therapeutic radioligands.