Fibroblast activation protein (FAP) is overexpressed in cancer-associated fibroblasts (CAFs) in a majority of human epithelial cancers. With low expression in normal organs, FAP has become a promising molecular target for tumor theranostics. To develop a lower cost and more widely available alternative to positron emission tomography (PET), two isocyanide-containing FAP inhibitors (CN-C5-FAPI and CN-PEG4-FAPI) were synthesized and radiolabeled with 99mTc to obtain [99mTc][Tc-(CN-C5-FAPI)6]+ and [99mTc][Tc-(CN-PEG4-FAPI)6]+ in high yields (>95%). They showed good stability in saline and mouse serum. The partition coefficient (log P) values of [99mTc][Tc-(CN-C5-FAPI)6]+ and [99mTc][Tc-(CN-PEG4-FAPI)6]+ were −0.86 ± 0.03 and −2.38 ± 0.07, respectively, indicating that they were good hydrophilic complexes. The low nanomolar IC50 values of CN-C5-FAPI and CN-PEG4-FAPI indicated that they had specificity to FAP. In vitro cellular uptake and blocking experiments implied a FAP-targeted uptake mechanism. The nanomolar K d values from the saturation binding assay indicated that they had significantly high target affinity to FAP. The biodistribution and blocking study in BALB/c nude mice bearing U87MG tumors showed that both exhibited specific tumor uptake. [99mTc][Tc-(CN-PEG4-FAPI)6]+ showed a higher tumor uptake and a higher tumor/nontarget ratio than [99mTc][Tc-(CN-C5-FAPI)6]+. The results of micro-single-photon emission computed tomography (SPECT) imaging studies of [99mTc][Tc-(CN-C5-FAPI)6]+ and [99mTc][Tc-(CN-PEG4-FAPI)6]+ were in accordance with the biodistribution results, suggesting that [99mTc][Tc-(CN-PEG4-FAPI)6]+ is a promising tumor imaging agent for targeting FAP.
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.
To develop novel radiolabeled amino acid tumor imaging agents, 4-methoxy-L-phenylalanine dithiocarbamate (MOPADTC) was synthesized successfully, and two kinds of 99mTc-labeled complexes ([99mTc]TcN-MOPADTC and [99mTc]TcO-MOPADTC) with high radiochemical purities (RCP > 95%) were obtained. The in vitro stability and partition coefficient were determined, and the results show that both of these complexes have good in vitro stability; [99mTc]TcO-MOPADTC is hydrophilic, while [99mTc]TcN-MOPADTC is slightly lipophilic. The biodistribution of [99mTc]TcN-MOPADTC and [99mTc]TcO-MOPADTC in mice bearing S180 tumors shows that the tumor uptake and tumor/muscle ratio of [99mTc]TcO-MOPADTC were higher than the tumor uptake and tumor/muscle ratio of [99mTc]TcN-MOPADTC. In addition, the tumor retention of [99mTc]TcO-MOPADTC is better than the tumor retention of [99mTc]TcN-MOPADTC. A competitive inhibition assay was performed, and the results indicate that [99mTc]TcO-MOPADTC may enter cells primarily via the L-alanine/L-serine/L-cysteine (ASC) system. Single-photon emission computed tomography (SPECT) imaging of [99mTc]TcO-MOPADTC shows obvious accumulation in tumor sites, suggesting that [99mTc]TcO-MOPADTC is a novel potential tumor-imaging agent.
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