Physicochemical properties of the high-field MRI-relevant [Gd(DTTA-Me)(H2O)2]- complex

To study the physicochemical properties of the DTTA chelating moiety (H(4)DTTA = 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 H(4)DTTA-Me (N,N'-[(methylimino)bis(ethane-2,1-diyl)]bis[N-(catoxymethyl)glycine]) was synthesized. Protonation constants of the ligand were determined in an aqueous solution by potentimetry and H-1 NMR pH titration and compared to various DTTA derivatives. Stability constants were measured for the chelates formed with Gd3+ (log K-GdL = 18.60 +/- 0.10) and Zn2+ (log K-ZnL = 17.69 +/- 0.10). A novel approach of determining the relative conditional stability constant of two paramagnetic complexes in a direct way by I H NMR relaxometry is presented and was used for the Gd3+ complexes [Gd(DTTA-Me)(H2O)(2)](-) (L-1) and [Gd(DTPA-BMA)(H2O)] (L-2) [KL1/L-2*(at pH 8.3, 25 degrees 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-BMA(3-). 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 H-1 NMR relaxometric titrations. From the results, it was concluded that the heptadentate DTTA-Me4- behaves similarly to the commercial octadentate DTPA-BMA(3-) 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.