[Tc-99m(N)PNP]-scaffold for SPECT of multidrug resistance: Early in-vitro study

99mTc(N)-DBODC(PNP5) [DBODC = bis(N-ethoxyethyl)dithiocarbamato; PNP5 = bis(dimethoxypropylphosphinoethyl)ethoxyethylamine] is a cationic mixed-compound, originally investigated as myocardial imaging agent, identified as suitable scaffold to devise 99mTc-agents for SPECT of multidrug resistance (MDR). To evaluate the impact of the [99mTc(N)PNP]-moiety on the tumor cell accumulation and on MDR recognition, different 99mTc(N)-DBODC(PNP5) like complexes were synthesized varying the substituents on the PNP ligand [PNPn = PNP3 bis(dimethoxypropylphosphinoethyl)-methoxyethylamine; PNP7 (bis(dimethoxyethylphosphinoethyl)-ethoxyethylamine); PNP10 (bis(dimethoxyethylphosphinoethyl)-methoxyethylamine)]. The 99mTc(N)-DBODC(PNPn) uptake was evaluated in human cancer cell lines (MCF7 and MCF7/ADR), and in the corresponding sub-lines using 99mTc-sestamibi and 99mTc(N)-DBODC(PNP5) as references. A significant increase of %cell-uptake of 99mTc(N)-DBODC(PNP7) and 99mTc(N)-DBODC(PNP10) was observed in drug-sensitive cell lines with respect to 99mTc-sestamibi and 99mTc(N)DBODC(PNP5). This amount was two and three times the %cell-uptake of the reference compounds. A reduction of the net cell uptake between drug-sensitive and drug-resistant cell lines was detected (p < 0.001). Changing chemical-physical properties of [99mTc(N)PNP]-moiety significantly affects the capability of the complexes to cross the plasma membrane increasing their %cell-uptake and affinity for MDR transporters. 99mTc(N)-DBODC(PNP7) and 99mTc(N)-DBODC(PNP10) are good candidates for in-vivo exploration of MDR. This research was supported by MIUR (PRIN 20097FJHPZ-004) and by AIRC (IG-13121).