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 in vitro 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 in vivo stability, and safety. Therefore, [99mTc]Tc-6-1 holds great potential as a promising molecular tracer for FAP tumor imaging.