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 (1)H NMR pH titration and compared to various DTTA derivatives. Stability constants were measured for the chelates formed with Gd(3+) (log K(GdL) = 18.60 +/- 0.10) and Zn(2+) (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 (1)H NMR relaxometry is presented and was used for the Gd(3+) complexes [Gd(DTTA-Me)(H2O)2](-) (L1) and [Gd(DTPA-BMA)(H2O)] (L2) [K(L1/L2)*(at pH 8.3, 25 degrees C) = 6.4 +/- 0.3]. The transmetalation reaction of the Gd(3+) complex with Zn(2+) 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 Zn(2+) toward DTTA-Me(4-) 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 (1)H NMR relaxometric titrations. From the results, it was concluded that the heptadentate DTTA-Me(4-) 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.
Moriggi
Loïck
L
Ecole Polytechnique Fédérale de Lausanne, Institut des sciences et ingénierie chimiques, EPFL-BCH, CH-1015 Lausanne, Switzerland.
Cannizzo
Caroline
C
Prestinari
Cora
C
Berrière
Florent
F
Helm
Lothar
L
D003287:Contrast Media / Q000138:chemical synthesis* / Q000737:chemistry; D017666:Deuterium Oxide / Q000737:chemistry; D019344:Lactic Acid / Q000737:chemistry; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D011199:Potentiometry; D015032:Zinc / Q000737:chemistry
D003287:Contrast Media; D009942:Organometallic Compounds; C533496:diaqua(N,N'-((methylimino)bis(ethane-2,1-diyl))bis(N-(carboxymethyl)glycine))gadolinate(III); D019344:Lactic Acid; D015032:Zinc; D017666:Deuterium Oxide