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

Abstract

ABSTRACT 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 68 Ga 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 68 Ga‐TH2103‐100 was >97%. In vitro experiments demonstrated that 68 Ga‐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 68 Ga‐TH2103‐100 exhibited promising diagnostic performance compared to 18 F‐FDG. The LARM‐based 68 Ga‐TH2103‐100 enables efficient room‐temperature labeling and superior tumor targeting, providing complementary diagnostic value for cases with inconclusive 18 F‐FDG PET/CT findings and offering a new paradigm for next‐generation FAP‐targeted molecular imaging agents, while its potential as an adjunct to 18 F‐FDG warrants further validation.