Synthesis and Preclinical Evaluation of Novel 99mTc-Labeled FR-Targeting Agents with Satisfactory Imaging Contrast and Reduced Renal Uptake

The folate receptor is overexpressed in a variety of epithelial-derived malignant cells. Several folate-based tracers have shown the ability to target FR, but excessive renal uptake is a general concern. To decrease renal uptake and achieve high target-to-nontarget ratios, two folate derivatives (DProFA and DAlaFA) were designed and synthesized. Eight complexes with high labeling yields and good in vitro stability were obtained by radiolabeling with technetium-99m and different coligands. The results of both in vitro cell and in vivo normal mice biodistribution studies demonstrated specific binding of eight complexes to the FR. Among them, [99mTc]Tc-DProFA-L1 exhibited lower off-target uptake and high tumor uptake in tumor-bearing mice, and significant inhibition in the biodistribution and SPECT/CT imaging study. The lower renal uptake of [99mTc]Tc-DProFA-L1 may prevent irradiation damage to the kidney. Consequently, [99mTc]Tc-DProFA-L1 is a highly promising candidate probe for the diagnosis of epithelial tumors in clinical nuclear medicine.