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

Alessandra      Boschi; Licia      Uccelli; Micol      Pasquali; Roberto      Pasqualini; Remo      Guerrini; Adriano      Duatti

Abstract

A new molecular metallic fragment for labeling biologically active molecules with ^99mTc and ¹⁸⁸Re is described. This system is composed of a combination of tridentate π-donor and monodentate π-acceptor ligands bound to a [M Ξ 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 Ξ N]²⁺ group (M = ^99mTc, ¹⁸⁸Re). In the resulting complexes (dubbed3+1complexes), the tridentate ligand binds the [MΞN]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 ^99mTc and ¹⁸⁸Re compounds was established by comparison with the chromatographic properties of the corresponding complexes obtained at the macroscopic level with the long–lived ^99gTc 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 π-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 ^99mTc and ¹⁸⁸Re. Thus, the new chelating system can be conveniently employed for labeling peptides and other biomolecules with the [MΞN]²⁺ group.