Synthesis and Preclinical Evaluation of Novel ^99mTc-Labeled FAPI-46 Derivatives with Significant Tumor Uptake and Improved Tumor-to-Nontarget Ratios

Abstract

Fibroblast activation protein (FAP), which is expressed on the cell membranes of fibroblasts in most solid tumors, has become an important target for tumor diagnosis and treatment. However, previously reported ^99mTc-labeled FAPI-04 complexes have high blood uptake, limiting their use in the clinic. In this work, six ^99mTc-labeled FAPI-46 derivatives with different linkers (different amino acids, peptides, or polyethylene glycol) were prepared and evaluated. They had good <i>in vitro</i> stability, hydrophilicity, and good specificity for FAP. The biodistribution and MicroSPECT images revealed that they all had high specific tumor uptake for FAP, and their blood uptake was significantly decreased. Among them, [^99mTc]Tc-6-1 exhibited the highest target-to-nontarget ratios (tumor/blood: 6.06 ± 1.19; tumor/muscle: 10.26 ± 0.44) and good tumor uptake (16.15 ± 0.83%ID/g), which also had significantly high affinity for FAP, good <i>in vivo</i> stability, and safety. Therefore, [^99mTc]Tc-6-1 holds great potential as a promising molecular tracer for FAP tumor imaging.