Synthesis, characterization, and biological evaluation of technetium(III) complexes with tridentate/bidentate S,E,S/P,S coordination (E = O, N(CH3), S): A novel approach to robust technetium chelates suitable for linking the metal to biomolecules

A novel type of mixed-ligand Tc(III) complexes, [Tc(SCH2CH2-E-CH2CH2S)(PR2S)] (E = S, N(CH3); PR2S = phosphinothiolate with R = aryl, alkyl) is described. These 3+2-coordinated complexes can be prepared in a two-step reduction/substitution procedure via the appropriate chloro-containing oxotechnetium(V) complex [TcO(SES)Cl] {E = S, N(CH3)}. Tc(III) compounds have been fully characterized both in solid and solution states and found to adopt the trigonal-bipyramidal coordination geometry. The equatorial trigonal plane is formed by three thiolate sulfur atoms, whereas the phosphorus of the bidentate P,S ligand and the neutral donor of the tridentate chelator occupy the apical positions. The Tc-99(III) complexes have been proven to be identical with the Tc-99m agents prepared at the no-carrier-added level by comparison of the corresponding UV/vis and radiometric HPLC profiles. Challenge experiments with glutathione clearly indicate that this tripeptide has no effect on the stability of the Tc-99m complexes in solutions. Biodistribution studies have been carried out in rats at 5 and 120 min postinjection. The substituents at the bidentate P,S ligand significantly influence the biodistribution pattern. Remarkable differences are observed especially in brain, blood, lungs, and liver. All the complexes are able to penetrate the blood-brain barrier of rats and showed a relatively fast washout from the brain.