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

Abstract

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.

Stability and Toxicity of Contrast Agents

“…The Mn 2+ complex of a DO3A analog where an oxygen donor is substituted for one of the macrocyclic ring nitrogens also shows decreased stability likely due to the lower total basicity of the ligand. The ligand AAZTA, which does not belong to any of the traditional ligand categories, was explored recently as a manganese chelator and showed acceptable affinity toward Mn 2+ [84]. The absence of an inner-sphere water molecule in Mn(AAZTA) 2− motivated the development of derivatives with reduced denticity [83].…”

“…The rates of this type of transmetallation reactions were found to be inversely proportional to the stability constants of the complexes [225]. The kinetics of metal exchange reactions between Gd 3+ complexes of AAZTA, DTPA, and DTPA derivatives in the presence of excess Cu 2+ , Zn 2+ , or Eu 3+ have been investigated more recently [23,30,62,84,226]. Under these conditions, the exchange reactions are pseudo-first-order and the rates can be expressed by Equation (4.8), where k d is a pseudo-first-order rate constant and [Ln(L)] t is the total concentration of the complex:…”

“…The sufficiently high stability constant of Gd(AAZTA)(H 2 O) 2 − (log K Gd(L) = 19.3 and 20.24) made this new ligand an attractive platform in the development of a novel class of MRI CAs[79,84].…”

Preparation, crystallographic and theoretical study on a bifunctional Gd-AAZTA derivative as potential MRI contrast agent precursor

“…More recently the AAZTA derivatives (AAZTA = 1,4-bis(carboxymethyl)-6-[bis(carboxymethyl)]-amino-6-methyl-1,4-diazepane) [11] were proposed, showing a good compromise between higher metal hydration and a good thermodynamic and an excellent kinetic stability [12]. The AAZTA ligand is formed by a seven-membered ring with two endocyclic and one exocyclic nitrogen atoms and four carboxymethyl side arms, representing a novel intermediate family between the open chain DTPA and macrocyclic DOTA ligands.…”

Improving the relaxivity by dimerizing Gd-AAZTA: Insights for enhancing the sensitivity of MRI contrast agents

“…The increase of r 1p has to be ascribed to the presence of two coordinated water molecules in the inner coordination sphere of the Gd(III) ion. Furthermore, it has been shown that Gd-AAZTA displays a very good stability (log K f = 20.2) [2] and very limited aptitude to transmetallation in the presence of Cu 2+ and Zn 2+ ions. The easy preparation of AAZTA ligand is another attractive property and several derivatives have been reported [3][4][5][6].…”