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=CH) and R'-S-CH₂CH₂-S-R' (R' = CH₃CH₂-, CH₃CH₂-OH, CH₂COOH) in methanol to form stable rhenium(I) tricarbonyl complexes of the general composition [ReBr(CO)₃L]. 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=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)]NO₃ 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 non-coordinated offering an ideal site for functionalization or coupling a biomolecule.
The no-carrier-added preparation of the analogue ^99mTc(I) carbonyl thioether complexes could be performed using the precursor fac-[99mTc(H₂O)₃(CO)₃]⁺
with yields up to 90 %. The behaviour of the chlorine containing ^99mTc complex ^[99mTcCl(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 [^99mTc(H₂O)(CO)₃(CH₃CH₂-S-CH₂CH₂-S-CH₂CH₃)]⁺ occured. 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 [^99mTcCl(CO)₃(CH₃CH₂-S-CH₂CH₂-S-CH₂CH₃)] Tc1 and [^99mTcCl(CO)₃(CH₂-S-CH₂CH₂-S-CH₂-C=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.