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

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, c_GdL = 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 (k_ex²⁹⁸ = (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 OPDMA^4-, while one carboxylate group remains uncoordinated.