Underlining the Importance of Peripheral Protic Functional Groups to Enhance the Proton Exchange of Gd-Based MRI Contrast Agents

In this study, we report the synthesis and the equilibrium, kinetic, relaxation, and structural properties of two new Gd^III complexes based on modified 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (HPDO3A) designed to modulate the relaxivity at acidic and basic pH due to intra- and intermolecular proton exchange. The presence of a carboxylic or ester moieties in place of the methyl group of HPDO3A allowed differentiation of a protic and nonprotic functional group, highlighting the importance of the formation of an intramolecular hydrogen bond between the coordinated hydroxyl and the carboxylate groups for proton exchange (k_H = 1.5 × 10¹¹ M^-1 s^-1, k_OH = 1.7 × 10⁹ M^-1 s^-1). The determination of the thermodynamic stability and kinetic inertness of the Gd^III complexes confirmed that the modification of peripheral groups does not significantly affect the coordination environment and thus the stability (log K_GdL = 19.26, t_1/2 = 2.14 × 10⁷ hours, pH = 7.4, 0.15 M NaCl, 25 °C). The relaxivity (r₁) was measured as a function of pH to investigate the proton exchange kinetics, and as a function of the magnetic field strength to extrapolate the relaxometric parameters (r₁^GdL1 = 4.7 mM^-1 s^-1 and r₁^GdL2 = 5.1 mM^-1 s^-1 at 20 MHz, 25 °C, and pH 7.4). Finally, the X-ray crystal structure of the complex crystallized at basic pH showed the formation of a tetranuclear dimer with alkoxide and hydroxide groups bridging the Gd^III ions.