Bipyridil-based chelators for Gd(iii) complexation: kinetic, structural and relaxation properties

In the last 20 years, research in the field of MRI (magnetic resonance imaging) contrast agents (CAs) has been intensified due to the emergence of a disease called nephrogenic systemic fibrosis (NSF). NSF has been linked to the in vivo dissociation of certain Gd(III)-based compounds applied in MRI as CAs. To prevent the dechelation of the probes after intravenous injection, the improvement of their in vivo stability is highly desired. The inertness of the Gd(III) chelates can be increased through the rigidification of the ligand structure. One of the potential ligands is (2,2',2'',2'''-((2,2'-bipyridine-6,6'-diylbis(methylene))bis(azanetriyl))tetraacetic acid) (H4DIPTA), which has been successfully used as a fluorescent probe for lanthanides; however, it has never been considered as a potential chelator for Gd(III) ions. In this paper, we report the thermodynamic, kinetic and structural features of the complex formed between Gd(III) and DIPTA. Since the solubility of the Gd(DIPTA)- chelate is very low under acidic conditions, hampering its thermodynamic characterization, we can only assume that its stability is close to that determined for the structural analogue Gd(FENTA)- (H4FENTA: (1,10-phenanthroline-2,9-diyl)bis(methyliminodiacetic acid)), which is similar to that determined for the agent Gd(DTPA)2- routinely used in clinical practice. Unfortunately, the inertness of Gd(DIPTA)- is significantly lower (t1/2 = 1.34 h) than that observed for Gd(EGTA)- and Gd(DTPA)2- as a result of its spontaneous dissociation pathway during dechelation. The relaxivity values of Gd(DIPTA)- are comparable with those of Gd(FENTA)- and somewhat higher than the values characterizing Gd(DTPA)2-. Luminescence lifetime measurements indicate the presence of one water molecule (q = 1) in the inner sphere of the complex with a relatively high water exchange rate (k298ex = 43(5) × 106 s-1). DFT calculations suggest a rigid distorted tricapped trigonal prismatic polyhedron for the Gd(III) complex. On the basis of these results, we can conclude that the bipyridine backbone is not favourable with respect to the inertness of the chelate.