Ruan_2023_J.Med.Chem_66_4952

Fibroblast activation protein (FAP) is a potential target for tumor diagnosis and treatment due to its selective expression on cancer-associated fibroblasts (CAFs) in most solid tumor stroma. Two FAP inhibitor (FAPI) derived ligands (L1 and L2) containing different lengths of (D)Pro-Gly (PG) repeat units as linkers were designed and synthesized with high affinity for FAP. Two stable hydrophilic (99m)Tc-labeled complexes ([(99m)Tc]Tc-L1 and [(99m)Tc]Tc-L2) were obtained. In vitro cellular studies show that the uptake mechanism is correlated with FAP uptake, and [(99m)Tc]Tc-L1 shows a higher cell uptake and specific binding to FAP. A nanomolar K(d) value for [(99m)Tc]Tc-L1 indicates its significantly high target affinity for FAP. The biodistribution and microSPECT/CT images obtained for U87MG tumor mice show that [(99m)Tc]Tc-L1 has high tumor uptake with specificity to FAP and high tumor-to-nontarget ratios. As an inexpensive, easily made, and widely available tracer, [(99m)Tc]Tc-L1 holds great promise for clinical applications.