Synthesis and Evaluation of <sup>99m</sup>Tc-Labeled FAP Inhibitors with Different Linkers for Imaging of Fibroblast Activation Proteins in Tumors
Qing Ruan, Qianna Wang, Yuhao Jiang, Junhong Feng, Guangxing Yin, Junbo Zhang
Abstract
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.