PEGylated N-methyl-S-methyl dithiocarbazate as a new reagent for the high-yield preparation of nitrido Tc-99m and Re-188 radiopharmaceuticals

A novel nitrido nitrogen atom donor for the preparation of Tc-99m and Re-188 radiopharmaceuticals containing a metal-nitrogen multiple bond is presented. HO2C-PEG(600)-DTCZ was obtained by conjugation of N-methyl-S-methyl dithiocarbazate [H2N-N(CH3)-C( S)SCH3, HDTCZ] with polyethylene glycol 600 (PEG(600)). Asymmetrical heterocomplexes of the type [M(N)(PNP)(B)](0/+) (M=Tc-99m, Re-188; PNP=diphosphine ligands, B=DBODC, DEDC, NSH, H2OS, CysNAc, HDTCZ) and symmetrical nitride compounds of the type [M(N)(L)(2)] (L=DEDC, DPDC) have been prepared in high yield by using the newly designed nitride nitrogen atom donor HO2C-PEG(600)-DTCZ. A two-step procedure was applied for preparing the above symmetrical and asymmetrical complexes. The first step involved the preliminary formation of a mixture of nitride Tc-99m or Re-188 precursors, which contained the [M N](2+) core, through reduction of generator-eluted Tc-99m-pertechnetate or Re-188-perrhenate with thin (11) chloride in the presence of HO2C-PEG(600)-DTCZ. In the second step, the intermediate mixture was converted either in the final mixed asymmetrical complex by the simultaneous addition of diphosphine ligand and the suitable bidentate ligand B, or in the final symmetrical complex by the only addition of the bidentate ligand L. It was also demonstrated that the novel water-soluble nitride nitrogen atom donor HO2C-PEG(600)-DTCZ did not show coordinating properties toward the M N (Tc-99m, Re-188) core. Biodistribution studies in rats of the hitherto unreported [Tc-99m(N)(PNP3)DTCZ](+) and [Tc-99m(N)(PNP5)DTCZ](+) complexes showed that they selectively localize in the myocardium of rats with a favourable heart-to-lung and heart-to-liver uptake ratios. In particular, the heart-to-lung and heart-to-liver uptake ratios dramatically increased in the interval between 60 and 120 min postinjection. Hence, the combination of the favourable chemical and biological properties of HO2C-PEG(600)-DTCZ might confer to this novel compound an important role for the development of new Tc-99m and Re-188-nitrido radiopharmaceuticals. (C) 2010 Elsevier Inc. All rights reserved.