Mono-, bi-, and trinuclear bis-hydrated Mn(2+) complexes as potential MRI contrast agents

We report a series of ligands containing pentadentate 6,6′-((methylazanediyl)bis(methylene))dipicolinic acid binding units that form mono- (H2dpama), di- (mX(H2dpama)2), and trinuclear (mX(H2dpama)3) complexes with Mn2+ containing two coordinated water molecules per metal ion, which results in pentagonal bipyramidal coordination around the metal ions. In contrast, the hexadentate ligand 6,6′-((ethane-1,2-diylbis(azanediyl))bis(methylene))dipicolinic acid (H2bcpe) forms a complex with distorted octahedral coordination around Mn2+ that lacks coordinated water molecules. The protonation constants of the ligands and the stability constants of the Mn2+, Cu2+, and Zn2+ complexes were determined using potentiometric and spectrophotometric titrations in 0.15 M NaCl. The pentadentate dpama2– ligand and the di- and trinucleating mX(dpama)24– and mX(dpama)36– ligands provide metal complexes with stabilities that are very similar to that of the complex with the hexadentate ligand bcpe2–, with log β101 values in the range 10.1–11.6. Cyclic voltammetry experiments on aqueous solutions of the [Mn(bcpe)] complex reveal a quasireversible system with a half-wave potential of +595 mV versus Ag/AgCl. However, [Mn(dpama)] did not suffer oxidation in the range 0.0–1.0 V, revealing a higher resistance toward oxidation. A detailed 1H NMRD and 17O NMR study provided insight into the parameters that govern the relaxivity for these systems. The exchange rate of the coordinated water molecules in [Mn(dpama)] is relatively fast, kex298 = (3.06 ± 0.16) × 108 s–1. The trinuclear [mX(Mn(dpama)(H2O)2)3] complex was found to bind human serum albumin with an association constant of 1286 ± 55 M–1 and a relaxivity of the adduct of 45.2 ± 0.6 mM–1 s–1 at 310 K and 20 MHz.