Exploring a Rigid Macrocyclic Ligand Bearing Malonate Pendants for Gd(III) Complexation: the Coordination Chemistry of [Gd(OPDMA)].

The emergence of nephrogenic systemic fibrosis, clearly linked to the in vivo dissociation of Gd(III)-based MRI contrast agents (CA), has promoted intensive research to identify safe CA candidates. Towards this goal, we have designed the novel ligand H4OPDMA, which combines a rigidified macrocycle, low total ligand basicity, and malonate pendant arms to increase the number of donor atoms. Thanks to these design elements, H4OPDMA is capable of forming a Gd(III) chelate with high thermodynamic stability and kinetic inertness. Indeed, the conditional stability of [Gd(OPDMA)]- (pGd = 14.8; pH 7.4, cGdL = 10-5 M) calculated for physiological conditions is comparable to that of [Gd(DTPA)]2- (pGd = 15.6), and its dissociation half-life is estimated to be 3.2 years at 37 °C and pH 7.4, making it an exceptionally inert chelate. Moreover, the water proton relaxation enhancement efficacy of [Gd(OPDMA)]- (r1 = 4.5 mM-1 s-1, 25°C, 20 MHz) is similar to that of clinical MRI contrast agents. Luminescence lifetime measurements and 17O NMR data confirmed the presence of one water molecule in the inner sphere of the metal ion (q = 1), which undergoes relatively fast exchange (kex298 = (73 ± 12) × 106 s-1). The fast water exchange can likely be related to an associatively activated mechanism, as suggested by the negative activation entropy, ΔS⧧ = -(7 ± 1) J mol-1 K-1. In accordance with this, DFT calculations indicate an eight-coordinated structure for the Gd(III) ion, involving one water molecule and seven donor atoms of the OPDMA4-, while one carboxylate group remains uncoordinated.