Mono-, Bi-, and TrinUclear Bis-Hydrated Mn2+ Complexes as Potential MRI Contrast Agents

We report a series of ligands containing pentadentate 6,6'-((methylazanediyObis(methylene))dipicolinic acid binding units that form mono- (H(2)dpama), di- (mX(H(2)dpama)(2)), and trinudear (mX(H(2)dpama)(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 dpama(2-) ligand and the di- and trinudeating mX(dpama)(2)(4-) and mX(dpama)(3)(6-) ligands provide metal complexes with stabilities that are very similar to that of the complex with the hexadentate ligand bcpe2-, with log beta(101) 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 H-1 NMRD and O-17 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, k(ex)(298) = (3.06 +/- 0.16) X 10(8) s(-1). The trinudear [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) at 310 K and 20 MHz.