99mTc-Labeled Quinolone-Based Novel Skeletal Tracers for Tumor Visualization through Fibroblast Activation Protein

Fibroblast activation protein (FAP) has emerged as a prominent target for tumor diagnosis. Quinoline-based FAP PET tracers demonstrated clinical feasibility. However, there is a relative scarcity of clinical studies on 99mTc-labeled FAP SPECT tracers. The existing quinoline-derived 99mTc-FAPI tracer exhibits relatively low tumor uptake and suboptimal pharmacokinetic properties, which restrict its clinical application. Consequently, it is necessary to alter the pharmacophores to improve its druggability. In this study, a novel quinolone-based pharmacophore was developed by utilizing scaffold hopping and conformational constrained strategies. Serial screening and preclinical evaluations were conducted. The 99mTc-FAPI-YQ3 showed extremely high tumor uptake and excellent pharmacokinetic properties. Additionally, 99mTc-FAPI-YQ3 demonstrated reliable safety characteristics and clinical efficacy on four different oncology patients. In conclusion, 99mTc-FAPI-YQ3 was a promising radiotracer for FAP-targeted cancer diagnosis, shedding light on substantially advancing SPECT molecular imaging.