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

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Abstract
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, and 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)]NO3Re8 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 99mTc(I) carbonyl thioether complexes could be performed using the precursor fac-[99mTc(H2O)3(CO)3]+, with yields up to 90%. The behavior 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)]+ 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 [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.