Equilibrium and Kinetic Properties of the Lanthanoids(III) and Various Divalent Metal Complexes of the Heptadentate Ligand AAZTA

Towards improved kinetic stability: A detailed account of the complexation properties of the ligand 1,4-bis(hydroxycarbonylmethyl)-6-[bis(hydroxycarbonylmethyl)]amino-6-methylperhydro-1,4-diazepine (AAZTA; see figure) is reported. Its Gd3+ complex shows a kinetic stability superior to that of complexes formed by higher denticity ligands and opens the way for a new reference structure for MRI contrast agents. The heptadentate ligand 1,4-bis(hydroxycarbonylmethyl)-6-[bis(hydroxycarbonylmethyl)]amino-6-methylperhydro-1,4-diazepine (AAZTA) and its derivatives were recently reported to give stable complexes with Gd3+ with superior efficiency as MRI contrast agents. Nevertheless, only preliminary data are available on the coordination behavior of this interesting ligand. In this work, thermodynamic and kinetic stability data are determined for the formation of complexes with AAZTA and the lanthanoid metal ions, and other divalent metal ions of interest for this application. The AAZTA ligand binds the lanthanoid ions with log KML values of 17.53-21.85 with its affinity steadily increasing from La3+ to Lu3+, suggesting that the seven-membered skeleton is better suited to accommodate smaller metal ions. Even though the denticity is lower, the stability of the heavier lanthanoid complexes is comparable to those of the classical ligand diethylenetriaminepentaacetic acid (DTPA). The transmetalation reactions of [Gd(AAZTA)]- with Cu2+ and Eu3+ predominantly occur through proton-assisted dissociation of the complex. The role of the direct attack of Cu2+ or Eu3+ in the exchange reactions is limited, although the formation of dinuclear complexes decreases the proton-assisted dissociation. Near physiological conditions, [Gd(AAZTA)]- is significantly more inert than [Gd(DTPA)]2-, allowing its potentially safe use as contrast agent in magnetic resonance imaging.