Coordination Properties of GdDO3A-Based Model Compounds of Bioresponsive MRI Contrast Agents

We report a detailed characterization of the thermodynamic stability and dissociation kinetics of Gd³⁺ complexes with DO3A derivatives containing a (methylethylcarbamoylmethylamino)­acetic acid (<b>L</b>^<b>1</b>), (methylpropylcarbamoylmethylamino)­acetic acid (<b>L</b>^<b>2</b>), 2-dimethylamino-<i>N</i>-ethylacetamide (<b>L</b>^<b>3</b>), or 2-dimethylamino-<i>N</i>-propylacetamide (<b>L</b>^<b>4</b>) group attached to the fourth nitrogen atom of the macrocyclic unit. These ligands are model systems of Ca²⁺- and Zn²⁺-responsive contrast agents (CA) for application in magnetic resonance imaging (MRI). The results of the potentiometric studies (<i>I</i> = 0.15 M NaCl) provide stability constants with log <i>K</i>_GdL values in the range 13.9–14.8. The complex speciation in solution was found to be quite complicated due to the formation of protonated species at low pH, hydroxido complexes at high pH, and stable dinuclear complexes in the case of <b>L</b>^<b>1,2</b>. At neutral pH significant fractions of the complexes are protonated at the amine group of the amide side chain (log <i>K</i>_GdL×H = 7.2–8.1). These ligands form rather weak complexes with Mg²⁺ and Ca²⁺ but very stable complexes with Cu²⁺ (log <i>K</i>_CuL = 20.4–22.3) and Zn²⁺ (log <i>K</i>_ZnL = 15.5–17.6). Structural studies using a combination of ¹H NMR and luminescence spectroscopy show that the amide group of the ligand is coordinated to the metal ion at pH ∼8.5, while protonation of the amine group provokes the decoordination of the amide O atom and a concomitant increase in the hydration number and proton relaxivity. The dissociation of the complexes occurs mainly through a rather efficient proton-assisted pathway, which results in kinetic inertness comparable to that of nonmacrocyclic ligands such as DTPA rather than DOTA-like complexes