Synthesis, Preclinical Evaluation, and Clinical Application of the FAPI-Dimer Based on the LARM Platform

Fibroblast activation protein (FAP) is a promising pan-tumor target for theranostics, but current FAP-targeted radioligands are limited by insufficient tumor retention and suboptimal therapeutic doses. To address these challenges, we developed a novel LARM platform and synthesized the FAPI dimer TH2103-100. The radiochemical labeling efficiency of TH2103-100 with ⁶⁸Ga was nearly 100% at room temperature (radio-TLC), significantly surpassing that of FAPI-04 (35.28% at room temperature and 79% at 95°C). The radiochemical purity of ⁶⁸Ga-TH2103-100 was >97%. In vitro experiments demonstrated that ⁶⁸Ga-TH2103-100 exhibited superior cellular uptake and enhanced binding affinity. In vivo experiments showed that, compared with FAPI-04, tumor uptake was increased by 3.9-fold with prolonged retention and no significant toxicity. In healthy volunteers, the effective dose was 3.69E-02 mSv/MBq. Preliminary clinical studies showed that ⁶⁸Ga-TH2103-100 exhibited promising diagnostic performance compared to ¹⁸F-FDG. The LARM-based ⁶⁸Ga-TH2103-100 enables efficient room-temperature labeling and superior tumor targeting, providing complementary diagnostic value for cases with inconclusive ¹⁸F-FDG PET/CT findings and offering a new paradigm for next-generation FAP-targeted molecular imaging agents, while its potential as an adjunct to ¹⁸F-FDG warrants further validation.