Syntheses and evaluations of the methoxy modified 99mTc-labeled triphenyl phosphonium cations: Potential radiometallic probes for multidrug resistance detection

Abstract In order to develop novel radio-metal labeled probes for tumor multidrug resistance (MDR) detection, two [(C 5 H 4 -R) 99m Tc(CO) 3 ]-triphenylphosphonium (TPP) cations with methoxy groups, 99m Tc-6 and 99m Tc-7 were prepared from the ferrocenyl precursors and purified by Radio-HPLC. Corresponding Re compounds were also synthesized and characterized as structure-referenced congeners of 99m Tc-labeled complexes. The 99m Tc-labeled complexes were lipophilic and stable both in saline at room temperature and in mouse serum at 37 °C for 4 h. In vitro cell uptake assay showed that 99m Tc-6 and 99m Tc-7 had a higher accumulation in the MDR-negative U87 tumor cells than that in the MDR-positive MCF-7/ADR cells. Pre-treatment of verapamil, Cyclosporine A and MK571, the modulators of P-glycoprotein/MRP1 (the principal MDR transporters in humans), could significantly increase the radio-accumulation in MCF-7/ADR cells. In biodistribution study, the U87 tumor (MDR-) uptakes of 99m Tc-6 and 99m Tc-7 were 2.14 ± 0.31 %ID/g and 1.21 ± 0.46 %ID/g at 1 h post-injection respectively, which were significantly higher than those in MCF-7/ADR tumor (0.26 ± 0.16 %ID/g and 0.28 ± 0.06 %ID/g at 1 h post-injection). The results demonstrated both of the 99m Tc-labeled complexes were the substrates of P-gp/MRP1. The para -methoxy group modified TPP-based complex 99m Tc-6 may be more sensitive in tumor multidrug resistance detection.