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 Gd(3+) 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 K(ML) values of 17.53-21.85 with its affinity steadily increasing from La(3+) to Lu(3+), 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 Cu(2+) and Eu(3+) predominantly occur through proton-assisted dissociation of the complex. The role of the direct attack of Cu(2+) or Eu(3+) 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.

An integrated 1H and 17O NMR relaxometric study on model systems allowed to highlight that the Fe(III) complexes might represent the best alternative to Gd-based MRI contrast agents at the magnetic fields of current and future clinical scanners.

A detailed study of the structures, thermodynamic stabilities and kinetics of the dissociation of Ga3+, In3+ and Cu2+ complexes formed with the heptadentate ligand AAZTA is reported. The stability constants (log KML) of the AAZTA complexes of Ga3+, In3+ and Cu2+ are 22.18, 29.58 and 22.27, respectively, which suggests that the seven‐membered‐ring skeleton is suited to the accommodation of these metal ions. The solid‐state structure of [Cu(H2AAZTA)]·H2O shows a distorted octahedral coordination. The equatorial coordination sites of Cu2+ are occupied by one of the ring N atoms, a water O atom, one of the carboxylate O atoms and the N atom of the iminodiacetate moiety. The other ring N atom and the carboxylate O atom of the iminodiacetate moiety coordinate to the Cu2+ in the axial positions. In the pH range 4.5–8.5, Ga3+ is present in the form of the highly stable [Ga(AAZTA)OH]2– (log βGaLH–1 = 17.69) The exchange reactions of [Ga(AAZTA)OH]2– with Cu2+ and transferrin are very slow and mainly occur through the spontaneous dissociation of the complex close to physiological conditions. The half‐life for the dissociation of [Ga(AAZTA)OH]2– is t1/2 = 23 h at pH = 7.5 and 25 °C in 0.025 M NaHCO3 and 0.15 M NaCl. The high conditional stability, fast formation and sufficiently slow dissociation of [Ga(AAZTA)OH]2– represent promising properties for the complexation and diagnostic applications of radioactive Ga isotopes.

The kinetics of the metal exchange reactions between open-chain Gd(DTPA)(2-) and Gd(DTPA-BMA), macrocyclic Gd(DOTA)(-) and Gd(HP-DO3A) complexes, and Cu(2+)  ions were investigated in the presence of endogenous citrate, phosphate, carbonate and histidinate ligands in the pH range 6-8 in NaCl (0.15 M) at 25 °C. The rates of the exchange reactions of Gd(DTPA)(2-) and Gd(DTPA-BMA) are independent of the Cu(2+) concentration in the presence of citrate and the reactions occur via the dissociation of Gd(3+)  complexes catalyzed by the citrate ions. The HCO(3)(-)/CO(3)(2-) and H(2)PO(4)(-) ions also catalyze the dissociation of complexes. The rates of the dissociation of Gd(DTPA-BMA), catalyzed by the endogenous ligands, are about two orders of magnitude higher than those of the Gd(DTPA)(2-). In fact near to physiological conditions the bicarbonate and carbonate ions show the largest catalytic effect, that significantly increase the dissociation rate of Gd(DTPA-BMA) and make the higher pH values (when the carbonate ion concentration is higher) a risk-factor for the dissociation of complexes in body fluids. The exchange reactions of Gd(DOTA)(-) and Gd(HP-DO3A) with Cu(2+) occur through the proton assisted dissociation of complexes in the pH range 3.5-5 and the endogenous ligands do not affect the dissociation rates of complexes. More insights into the interaction scheme between Gd(DTPA-BMA) and Gd(DTPA)(2-) and endogenous ligands have been obtained by acquiring the (13)C NMR spectra of the corresponding diamagnetic Y(III)-complexes, indicating the increase of the rates of the intramolecular rearrangements in the presence of carbonate and citrate ions. The herein reported results may have implications in the understanding of the etiology of nephrogenic systemic fibrosis, a rare disease that has been associated to the administration of Gd-containing agents to patients with impaired renal function.