Chemical and biological characterization of technetium(I) and rhenium(I) tricarbonyl complexes with dithioether ligands serving as linkers for coupling the Tc(CO)3 and Re(CO)3 moieties to biologically active molecules

The organometallic precursor (NEt4)(2)[ReBr3(CO)(3)] was reacted with bidendate dithioethers (L) of the general formula H3C-S-CH2CH2-S-R (R = -CH2CH2COOH, CH2-C drop CH) and R'-S-CH2CH2-S-R' (R' = CH3CH2-, CH3CH2-OH, and CH2COOH) in methanol to form stable rhenium(I) tricarbonyl complexes of the general composition [ReBr(CO)(3)L]. Under these conditions, the functional groups do not participate in the coordination. As a prototypic representative of this type of Re compounds, the propargylic group bearing complex [ReBr(CO3)(H3C-S-CH2CH2-S-CH2C drop CH)] Re2 was studied by X-ray diffraction analysis. Its molecular structure exhibits a slightly distorted octahedron with facial coordination of the carbonyl ligands. The potentially tetradentate ligand HO-CH2CH2-S-CH2CH2-S-CH2CH2-OH was reacted with the trinitrato precursor [Re(NO3)(3)(CO)(3)](2-) to yield a cationic complex [Re(CO)(3)(HO-CH2CH2-S-CH2CH2-S-CH2CH2-OH) Re8 which shows the coordination of one hydroxy group. Re8 has been characterized by correct elemental analysis, infrared spectroscopy, capillary electrophoresis, and X-ray diffraction analysis. Ligand exchange reaction of the carboxylic group bearing ligands H3C-S-CH2CH2-S-CH2CH2-COOH and HOOC-CH2-S-CH2CH2-S-CH2-COOH with (NEt4)(2)[ReBr3(CO)(3)] in water and with equimolar amounts of NaOH led to complexes in which the bromide is replaced by the carboxylic group. The X-ray structure analysis of the complex [Re(CO)(3)(OOC-CH2-S-CH2CH2-S-CH2-COOH)] Re6 shows the second carboxylic group noncoordinated offering an ideal site for functionalization or coupling a biomolecule. The no-carrier-added preparation of the analogous Tc-99m(I) carbonyl thioether complexes could be performed using the precursor fac-[Tc-99m(H2O)(3)(CO)(3)](+), with yields up to 90%. The behavior of the chlorine containing Tc-99m complex [(TcCl)-Tc-99m(CO)(3)(CH3CH2-S-CH2CH2-S-CH2CH3)] Tc1 in aqueous solution at physiological pH value was investigated. In saline, the chromatographically separated compound was stable for at least 120 min. However, in chloride-free aqueous solution, a water-coordinated cationic species Tc1a of the proposed composition[Tc-99m(H2O)(CO)(3)(CH3CH2-S-CH2CH2-S-CH2CH3)](+) occurred. The cationic charge of the conversion product was confirmed by capillary electrophoresis. By the introduction of a carboxylic group into the thioether Ligand as a third donor group, the conversion could be suppressed and thus the neutrality of the complex preserved. Biodistribution studies in the rat demonstrated for the neutral complexes [(TcCl)-Tc-99m(CO)(3)(CH3CH2-S-CH2CH2-S-CH2CH3)] Tc1 and [(TcCl)-Tc-99m(CO)(3)(CH2-S-CH2CH2-S-CH2-C drop CH)] Tc2 a significant initial brain uptake (1.03 +/- 0.25% and 0.78 +/- 0.08% ID/organ at 5 min. p.i.). Challenge experiments with glutathione clearly indicated that no transchelation reaction occurs in vivo.