Development of a Novel ^99mTc-Labeled Folate Derivative Containing Phenyl Isonitrile to Target Folate Receptor with Reduced Renal Uptake

The folate receptor has attracted much attention in the field of radiolabeled imaging agents due to the significant difference in its expression levels between tumor cells and most normal cells. However, the development of folate-based imaging agents has been limited by their high uptake in the kidney. In this study, to reduce the high renal uptake of radiolabeled folate-based tracers, a phenyl-isonitrile folate derivative (CNMBFA) was designed and labeled with technetium-99m. The complex obtained <i>via</i> the one-step kit labeling method had a high labeling yield (>95%) and high <i>in vitro</i> stability and hydrophilicity (log <i>D</i>_7.4 = -1.72 ± 0.13). The results of the <i>in vitro</i> cell uptake and blocking studies and competitive binding experiments revealed that the [[^99mTc]Tc-(CNMBFA)₆]⁺ complex was specific for the folate receptor. Biodistribution and inhibition studies in KB tumor-bearing mice revealed moderate uptake and significant inhibition of the complex in tumors, whereas the renal uptake of [[^99mTc]Tc-(CNMBFA)₆]⁺ was significantly lower than that of previously reported tracers. Micro-SPECT/CT images further supported its ability to target the folate receptor for tumor imaging. Taken together, these results indicate that [[^99mTc]Tc-(CNMBFA)₆]⁺ is a potential tumor imaging agent that has good tumor-targeting properties with minimal radiation damage to the kidney.