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

[Image: see text] 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 × 10(11) M(–1) s(–1), k(OH) = 1.7 × 10(9) 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 × 10(7) hours, pH = 7.4, 0.15 M NaCl, 25 °C). The relaxivity (r(1)) 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 (r(1)(GdL1) = 4.7 mM(–1) s(–1) and r(1)(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.