Synthesis and characterization of the novel monoamide derivatives of Gd-TTDA

For this study, the N'-monoamide derivatives of TTDA (3,6,10-tri(carboxymethyl)-3,6,10-triazadodecanedioic acid), N'-methylamide (TTDA-MA), N'-benzylamide (TTDA-BA), and N'-2-methoxybenzylamide (TTDA-MOBA), were synthesized. Their protonation constants and stability constants (log K(ML)'s) formed with Ca(2+), Zn(2+), Cu(2+), and Gd(3+) were determined by potentiometric titration in 0.10 M Me(4)NCl at 25.0 +/- 0.1 degrees C. The relaxivity values of Gd(TTDA-MA)](-), Gd(TTDA-BA)](-), and Gd(TTDA-MOBA)](-) remained constant with respect to pH changes over the range 4.5-12.0. The (17)O NMR chemical shift of H(2)O induced by Dy(TTDA-MA)(H(2)O)](-) at pH 6.80 showed 0.9 inner-sphere water molecules. Water proton relaxivity values for Gd(TTDA-MA)(H(2)O)](-), Gd(TTDA-BA)(H(2)O)](-), and Gd(TTDA-MOBA)(H(2)O)](-) at 37.0 +/- 0.1 degrees C and 20 MHz are 3.89, 4.21, and 4.25, respectively. The water-exchange lifetime (tau(M)) and rotational correlation time (tau(R)) of Gd(TTDA-MA)(H(2)O)](-), Gd(TTDA-BA)(H(2)O)](-), and Gd(TTDA-MOBA)(H(2)O)](-) are obtained from reduced the (17)O relaxation rate and chemical shifts of H(2)(17)O. The (2)H NMR longitudinal relaxation rates of the deuterated diamagnetic lanthanum complexes for the rotational correlation time were also thoroughly investigated. The water-exchange rates (K(298)(ex) for Gd(TTDA-MA)(H(2)O)](-), Gd(TTDA-BA)(H(2)O)](-), and Gd(TTDA-MOBA)(H(2)O)](-) are lower than that of Gd(TTDA)(H(2)O)](2)(-) but significantly higher than those of Gd(DTPA)(H(2)O)](2)(-) and Gd(DTPA-BMA)(H(2)O)]. The rotational correlation times for Gd(TTDA-BA)(H(2)O)](-) and Gd(TTDA-MOBA)(H(2)O)](-) are significantly longer than those of Gd(TTDA)(H(2)O)](2)(-) and Gd(DTPA)(H(2)O)](2)(-) complexes. The marked increase of the relaxivity of Gd(TTDA-BA)(H(2)O)](-) and Gd(TTDA-MOBA)(H(2)O)](-) results mainly from their longer rotational correlation time. The noncovalent interaction between human serum albumin (HSA) and Gd(TTDA-BA)(H(2)O)](-) and Gd(TTDA-MOBA)(H(2)O)](-) complexes containing a hydrophobic substituent was investigated by measuring the water proton relaxation rate of the aqueous solutions. The binding association constant (K(A)) values are 1.0 +/- 0.2 x 10(3) and 1.3 +/- 0.2 x 10(3) M(-1) for Gd(TTDA-BA)(H(2)O)](-) and Gd(TTDA-MOBA)(H(2)O)](-), which indicates a stronger interaction of Gd(TTDA-BA)(H(2)O)](-) and Gd(TTDA-MOBA)(H(2)O)](-) with HSA.