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 biden date dithioethers (L) of the general formula H3C-S-CH2CH2-S-R (R = -CH2CH2C OOH, CH2-C drop CH) and R'-S-CH2CH2-S-R' (R' = CH3CH2-, CH3CH2-OH, and CH2C OOH) in methanol to form stable rhenium(I) tricarbonyl complexes of the gen eral composition [ReBr(CO)(3)L]. Under these conditions, the functional gro ups do not participate in the coordination. As a prototypic representative of this type of Re compounds, the propargylic group bearing complex [ReBr(C O3)(H3C-S-CH2CH2-S-CH2C drop CH)] Re2 was studied by X-ray diffraction anal ysis. 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 precu rsor [Re(NO3)(3)(CO)(3)](2-) to yield a cationic complex [Re(CO)(3)(HO-CH2C H2-S-CH2CH2-S-CH2CH2-OH) Re8 which shows the coordination of one hydroxy gr oup. Re8 has been characterized by correct elemental analysis, infrared spe ctroscopy, capillary electrophoresis, and X-ray diffraction analysis. Ligan d 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)] i n water and with equimolar amounts of NaOH led to complexes in which the br omide 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 c arboxylic group noncoordinated offering an ideal site for functionalization or coupling a biomolecule. The no-carrier-added preparation of the analogo us Tc-99m(I) carbonyl thioether complexes could be performed using the prec ursor fac-[Tc-99m(H2O)(3)(CO)(3)](+), with yields up to 90%. The behavior o f the chlorine containing Tc-99m complex [(TcCl)-Tc-99m(CO)(3)(CH3CH2-S-CH2 CH2-S-CH2CH3)] Tc1 in aqueous solution at physiological pH value was invest igated. In saline, the chromatographically separated compound was stable fo r at least 120 min. However, in chloride-free aqueous solution, a water-coo rdinated cationic species Tc1a of the proposed composition[Tc-99m(H2O)(CO)( 3)(CH3CH2-S-CH2CH2-S-CH2CH3)](+) occurred. The cationic charge of the conve rsion product was confirmed by capillary electrophoresis. By the introducti on 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 p reserved. Biodistribution studies in the rat demonstrated for the neutral c omplexes [(TcCl)-Tc-99m(CO)(3)(CH3CH2-S-CH2CH2-S-CH2CH3)] Tc1 and [(TcCl)-T c-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 clearl y indicated that no transchelation reaction occurs in vivo.