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

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 H-1 nuclear magnetic relaxation dispersion (NMRD) study coupled with O-17 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 (rb(1) = 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).

Automated summary

This study highlights the importance of ligand topology in the properties of Gd(iii) complexes relevant in the field of magnetic resonance imaging (MRI). By comparing two Gd(iii) complexes, it was found that they have different hydration numbers, stability, kinetic inertness, and water exchange rates. Differences were also observed in their interaction and relaxivity with human serum albumin.