Mixed Tridentate pi-Donor and Monodentate pi-Acceptor Ligands as Chelating Systems for Rhenium-188 and Technetium-99m Nitrido Radiopharmaceuticals

A new molecular metallic fragment for labeling biologically active molecules with Tc-99m and Re-188 is described. This system is composed of a combination of tridentate pi-donor and monodentate pi-acceptor ligands bound to a [M N](2+) group (M = 99mTc, 188Re) in a pseudo square-pyramidal geometry. A simple structural model of the new metallic fragment was obtained by reacting the ligand 2, 2'-iminodiethanethiol [H2NS2 = NH(CH2CH2SH)(2)] and monodentate tertiary phosphines with the [M N](2+) group (M = Tc-99m, Re-188). In the resulting complexes (dubbed3+1complexes), the tridentate ligand binds the [M N](2+) core through the two deprotonated, negatively charged, thiol sulfur atoms and the neutral, protonated, amine nitrogen atom. The residual fourth position of the five-coordinated arrangement is occupied by a phosphine ligand. The chemical identity of these model Tc-99m and Re-188 compounds was established by comparison with the chromatographic properties of the corresponding complexes obtained at the macroscopic level with the long-lived Tc-99g and natural Re isotopes. The investigation was further extended to comprise a series of ligands formed by simple combinations of two basic amino acids or pseudo-amino acids to yield potential tridentate chelating systems having [S, N, S] and [N, N, S] as sets of pi-donor atoms. Labeling yields and in vitro stability were investigated using different ancillary ligands. Results showed that SNS-type ligands afforded the highest labeling yields and the most robust 3+1 nitrido complexes with both Tc-99m and Re-188. Thus, the new chelating system can be conveniently employed for labeling peptides and other biomolecules with the [M N](2+) group.