The critical role of ligand topology: strikingly different properties of Gd(iii) complexes with regioisomeric AAZTA derivatives

Abstract

The substitution of an acetate pendant arm on the endocyclic or exocyclic nitrogen atoms of AAZTA with a hydroxybenzyl group results in two regioisomeric Gd(III) complexes with different hydration numbers, thermodynamic stabilities differing by 5.5 log K units and remarkably different kinetic inertness. The ligand functionalized with the phenol group on the exocyclic N atom (AAZ3A-exoHB) forms a Gd(III) complex with remarkably high stability (log K_GdL = 25.06) thanks to the tight coordination of the phenol group, which presents a rather low protonation constant (log K_GdHL = 3.22). Conversely, the complex formed with the ligand bearing a phenol unit attached to an endocyclic N atom (AAZ3A-endoHB) is considerably less stable (log K_GdL = 19.57) and more prone to protonation (log K_GdHL = 6.22). Transmetallation kinetics studies in the presence of Cu(II) evidence that the Gd(III) complexes dissociate via the proton- and metal-assisted dissociation pathways, with the AAZ3A-exoHB derivative being considerably more inert. A detailed ¹H nuclear magnetic relaxation dispersion (NMRD) study coupled with ¹⁷O NMR measurements demonstrates that the complex with AAZ3A-exoHB contains a single water molecule in the inner coordination sphere, while the AAZ3A-endoHB analogue has two water molecules coordinated to the metal ion endowed with significantly different water exchange rates. Finally, a binding study of the two complexes with human serum albumin showed a stronger interaction and higher relaxivity (r^b₁ = 36.5 mM⁻¹ s⁻¹ at 30 MHz and 298 K) for Gd(AAZ3A-endoHB) than for Gd(AAZ3A-exoHB). Overall, this study highlights the importance that ligand topology has in the properties of Gd(III) complexes relevant in the field of magnetic resonance imaging (MRI).