Journal article

Physicochemical Properties of the High-Field MRI-Relevant [Gd(DTTA-Me)(H2O)2]− Complex

To study the physicochemical properties of the DTTA chelating moiety (H4DTTA = diethylenetriaminetetraacetic acid = N,N′-[iminobis(ethane-2,1-diyl)]bis[N-(carboxymethyl)glycine]), used in several compounds proposed as magnetic resonance imaging (MRI) contrast agents, the methylated derivative H4DTTA-Me (N,N′-[(methylimino)bis(ethane-2,1-diyl)]bis[N-(carboxymethyl)glycine]) was synthesized. Protonation constants of the ligand were determined in an aqueous solution by potentimetry and 1H NMR pH titration and compared to various DTTA derivatives. Stability constants were measured for the chelates formed with Gd3+ (log KGdL = 18.60 0.10) and Zn2+ (log KZnL = 17.69 0.10). A novel approach of determining the relative conditional stability constant of two paramagnetic complexes in a direct way by 1H NMR relaxometry is presented and was used for the Gd3+ complexes [Gd(DTTA-Me)(H2O)2]− (L1) and [Gd(DTPA-BMA)(H2O)] (L2) [KL1/L2*(at pH 8.3, 25 °C) = 6.4 0.3]. The transmetalation reaction of the Gd3+ complex with Zn2+ in a phosphate buffer solution (pH 7.0) was measured to be twice as fast for [Gd(DTTA-Me)(H2O)2]− in comparison to that for [Gd(DTPA-BMA)(H2O)]. This can be rationalized by the higher affinity of Zn2+ toward DTTA-Me4− if compared to DTPA-BMA3−. The formation of a ternary complex with L-lactate, which is common for DO3A-based heptadentate complexes, has not been observed for [Gd(DTTA-Me)(H2O)2]− as monitored by 1H NMR relaxometric titrations. From the results, it was concluded that the heptadentate DTTA-Me4− behaves similarly to the commercial octadentate DTPA-BMA3− with respect to stability. The use of [Gd(DTTA-Me)(H2O)2]− as an MRI contrast agent in vitro and in animal studies is conceivable, mainly at high magnetic fields, where an increase of the inner-sphere-coordination water actually seems to be the most certain way to increase the relaxivity.


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