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 sulfurs atoms, whereas the phosphorus of the bidendate P,S ligand and the neutral donor of the tridendate chelator occupy the apical positions. The 99Tc(III) complexes have been proven to be identical with the 99mTc-agents prepared at the no-carrier-added level by comparison of the corresponding UV-Vis and radiometric HPLC profiles. Challenge experiments with glutathione clearly indicated that this tripeptide has no effect on the stability of the 99mTc complexes in solutions. Biodistribution studies were carried out in rats at 5 and 120 minutes post injection. The substituents at the bidendate P,S ligand significantly influenced the biodistribution pattern. Remarkable differences were observed especially in brain, blood, lungs and liver. All the complexes were able to penetrate the blood-brain-barrier of rat brain and showed a relatively fast washout from the brain.