New N₃S Donor Ligand Small Peptide Analogues of the <i>N</i>-Mercaptoacetyl-glycylglycylglycine Ligand in the Clinically Used Tc-99m Renal Imaging Agent: Evidence for Unusual Amide Oxygen Coordination by Two New Ligands

Three new X-ray structurally characterized Re(V)O complexes, ReO(MEG3H2) (10), ReClO(MAEG2H3) (11), and {ReO(MECG2H2)}2 (12), were prepared from protected forms of three new ligands, mercaptoethyl-glycylglycylglycine (MEG3H5), mercaptoacetamide-ethyl-glycylglycine (MAEG2H5), and mercaptoethyl-carbamoylmethyl-glycylglycine (MECG2H5). (Subscript on H indicates the number of dissociable protons.) Mercaptoacetyltriglycine (MAG3H5) is the ligand precursor for the clinically used Tc-99m renal imaging agent. The new potentially N3S donor ligands have a glycylglycine carboxyl end as in MAG3H5, but a secondary amine (sp3 N) replaces one amide (sp2 N) of MAG3H5. ReO(MEG3H2) (10) is a typical five-coordinate pseudo-square-pyramidal complex with the oxo ligand at the apex and the trianionic form of MEG3H5 coordinated in the basal plane via N3S. In the other complexes, the quadridentate ligand has N2OS ligation, with the carbonyl oxygen of the glycyl amide group coordinated trans to the oxo ligand. This unusual ligation mode, which is facilitated by the preferred endo configuration of the ligated glycyl sp3 N, leaves a vacant basal coordination site. In 11, the chloro ligand completes the equatorial plane, whereas, in 12, a glycine carboxylate oxygen of the ligand on the partner Re completes the equatorial plane. Both complexes thus possess an unexpected pseudo-octahedral geometry. For 10, 11, and 12, the 1H NMR spectra, monitored from high to low pH, exhibited changes only when the pH was lowered below 6. This finding indicates that at physiological pH these complexes possess the desirable characteristic of existing as one monomeric species having only one ionization state, with the coordinated sp3 N deprotonated. Below pH 6 and above pH ∼4, changes in the 1H NMR shifts indicate that this sp3 N has become protonated. Thus, the N3S ligands in all three complexes exhibit normal coordination above pH ∼4. However, X-ray data for 11 and 12 and some NMR evidence for 11 indicate that the ligands of the two complexes rearrange at low pH (<3). The striking differences between the solution- and solid-state structures reinforce the caveat that solution structural studies conducted at physiological pH are necessary in order to gain insight into the nature of radiopharmaceuticals.