New bioconjugated rhenium carbonyls by transmetalation reaction with zinc derivatives

Abstract

The transmetallation reaction between zinc dithiocarbamates and rhenium carbonyls has been used as a new strategy to link biomolecules to transition metals. The zinc(II) dithiocarbamate of isonipecotic acid (1) and the succinimidyl ester derivative (2) were prepared by straight forward procedures and were fully characterized by spectroscopic and X-ray diffraction methods, showing in both cases the presence of dinuclear complexes. Complex 2 reacted with all the primary and secondary amines studied (glycine methyl ester, β-alanine methyl ester, 1-(2-methoxyphenyl)piperazine and D-(+)-glucosamine) through the activated succinimidyl ester group, linking the metallic fragment with the biomolecule by the formation of a peptidic bond, and leading to the respective bioconjugated zinc complexes 3-6. In all cases, these zinc complexes could be isolated from the reaction medium by simple precipitation. These results evidence the potential of complex 2 to be used as a synthon to link the zinc dithiocarbamate fragment to biomolecules that contain an amine group. Complexes 3-6 were characterized by the usual spectroscopic methods and all data agree with the proposed structures, which do not contain significant interactions between the zinc fragment and the functional groups of these biomolecules. The transmetallation reaction between the zinc complexes 3-6 and the rhenium carbonyl [ReBr₃(CO)₃]²⁻ led to the expected rhenium dithiocarbamates 7-10 with no change in the organic dithiocarbamate fragments, confirming the viability of this reaction as a tool for linking biomolecules to transition elements. All complexes were characterized by spectroscopic methods and the crystal structure of 8 was studied by X-ray diffraction analysis. All data demonstrated that the biomolecule is positioned far away from the fac-{Re(CO)₃} fragment and the octahedral coordination around the metal is completed by the functionalized dithiocarbamate and a phosphine ligand. Finally, the analysis by ESI-MS spectrometry of the reaction between the zinc complex 4 and a water solution of [Re(H₂O)₃(CO)₃]+ at a very low concentration (10 ppm) showed that the transmetallation reaction took place even though the solubility of the zinc complex in water medium was as low as 0.66 ppm. This preliminary result supports the viability of this approach for the preparation of rhenium and technetium target specific radiopharmaceuticals since the preparation of these compounds are always performed in water medium.