Physico-Chemical Characterization of a Highly Rigid Gd(III) Complex Formed with a Phenanthroline Derivative Ligand

The discovery of the nephrogenic systemic fibrosis (NSF) and its link with the in vivo dissociation of certain Gd(III)-based contrast agents (CAs) applied in the magnetic resonance imaging (MRI) induced a still growing research to replace the compromised agents with safer alternatives. In recent years, several ligands were designed to exploit the luminescence properties of the lanthanides, containing structurally constrained aromatic moieties, which may form rigid Gd(III) complexes. One of these ligands is (1,10-phenanthroline-2,9-diyl)bis(methyliminodiacetic acid) (H₄FENTA) designed and synthesized to sensitize Eu(III) and Tb(III) luminescence. Our results show that the conditional stability of the [Gd(FENTA)]^- chelate calculated for physiological pH (pGd = 19.7) is similar to those determined for [Gd(DTPA)]^2- (pGd = 19.4) and [Gd(DOTA)]^- (pGd = 20.1), routinely used in the clinical practice. The [Gd(FENTA)]^- complex is remarkably inert with respect to its dissociation (t_1/2 = 872 days at pH = 7 and 25 °C); furthermore, its relaxivity values determined at different field strengths and temperatures (e.g., r_1p = 4.3 mM^-1s^-1at 60 MHz and 37 °C) are ca. one unit higher than those of [Gd(DTPA)]^2- (r_1p = 3.4 mM^-1 s^-1) and [Gd(DOTA)]^- (r_1p = 3.1 mM^-1 s^-1) under the same conditions. Moreover, significant improvement on the relaxivity was observed in the presence of serum proteins (r_1p = 6.9 mM^-1 s^-1 at 60 MHz and 37 °C). The luminescence lifetimes recorded in H₂O and D₂O solutions indicate the presence of a water molecule (q = 1) in the inner sphere of the complex directly coordinated to the metal ion, possessing a relatively high water exchange rate (k_ex²⁹⁸ = 29(2) × 10⁶ s^-1). The acceleration of the water exchange can be explained by the steric compression around the water binding site due to the rigid structure of the complex, which was supported by DFT calculations. On the basis of these results, ligands containing a phenanthroline platform have great potential in the design of safer Gd(III) agents for MRI.