Synthesis and Evaluation of 99mTc-Labeled Dimeric Folic Acid for FR-Targeting

The folate receptor (FR) is overexpressed in a wide variety of human tumors. In our study, the multimeric concept was used to synthesize a dimeric folate derivative via a click reaction. The novel folate derivative (HYNIC-D-1-FA(2)) was radiolabeled with Tc-99m using tricine and trisodium triphenylphosphine-3,3',3 ''-trisulfonate (TPPTS) as coligands (Tc-99m-HYNIC-D-1-FA(2)) and its in vitro physicochemical properties, ex vivo biodistribution and in vivo micro-SPECT/CT imaging as a potential FR targeted agent were evaluated. It is a hydrophilic compound (log P = 2.52 +/- 0.13) with high binding affinity (IC50 = 19.06 nM). Biodistribution in KB tumor-bearing mice showed that Tc-99m-HYNIC-D-1-FA(2) had high uptake in FR overexpressed tumor and kidney at all time-points, and both of them could obviously be inhibited when blocking with free FA in the blocking studies. From the in vivo micro-SPECT/CT imaging results, good tumor uptake of Tc-99m-HYNIC-D-1-FA(2) was observed in KB tumor-bearing mice and it could be blocked obviously. Based on the results, this new radiolabeled dimeric FA tracer might be a promising candidate for FR-targeting imaging with high affinity and selectivity.