Synthesis of four derivatives of 3,6,10-tri(carboxymethyl)-3,6,10-triazadodecanedioic acid, the stabilities of their complexes with Ca(II), Cu(II), Zn(II) and lanthanide(III) and water-exchange investigations of Gd(III) chelates

The protonation constants of four poly( aminocarboxylates), N'-pyridylmethy l (TTDA-PY), N'-2-hydroxypropyl (TTDA-HP), N'-2-hydroxy-1-phenylethyl (TTDA -H1P) and N'-2-hydroxy-2-phenylethyl (TTDA-H2P) derivatives of TTDA (3,6,10 -tri(carboxymethyl)-3,6,10-triazadodecanedioic acid), and the stability con stants of their complexes formed with Ca2+, Zn2+, Cu2+, La3+, Ce3+, Nd3+, S m3+, Gd3+, Dy3+, Ho3+, Yb3+ and Lu3+ were determined by potentiometric meth ods at 25.0 +/- 0.1 degreesC and 0.10 mol dm(-3) ionic strength in Me4NNO3. The stability of the Gd(III) complexes follows the order TTDA-PY > TTDA-H2 P approximate to TTDA-HP approximate to TTDA-H1P. The thermodynamic resista nce of the gadolinium(III) complexes, at the plasma concentration used in c linical applications, towards demetallation in the presence of important co mponents of blood plasma, such as Ca(II), Zn(II) and Cu(II), has been evalu ated. The observed water proton relaxivity values of [Gd(TTDA- PY)](-), [Gd (TTDA-HP)](-), [Gd( TTDA-H1P)](-) and [Gd( TTDA-H2P)](-) became constant wi th respect to pH changes over the range of 4-10, 6-10, 6-10 and 6-10, respe ctively. O-17 NMR shifts showed that the [Dy(TTDA-PY)](-), [Dy(TTDA-HP)](-) , [Dy(TTDA-H1P)](-) and [Dy(TTDA-H2P)](-) complexes at pH 6.30 and 4.30 had 0.9 and 0.9; 2.2 and 3.4; 2.0 and 3.5; 1.8 and 3.0 inner-sphere water mole cules, respectively. Water proton spin-lattice relaxation rates for gadolin ium(III) complexes were also consistent with the number of inner-sphere wat er molecules. The EPR transverse electronic relaxation rate and O-17 NMR tr ansverse relaxation time were thoroughly investigated and the results obtai ned were compared with that previously reported for the other gadolinium(II I) complex, [Gd(DTPA)(H2O)](2-). Short exchange lifetime values were obtain ed for the [Gd(TTDA)(H2O)](2-), [Gd(TTDA-PY)(H2O)](-), [Gd(TTDA- HP)(H2O)(2 )](-), [Gd(TTDA-H1P)( H2O)(2)](-) and [Gd(TTDA-H2P)(H2O)(2)](-) complexes. Their water-exchange rates are about 24-45 times faster than that for the [ Gd(DTPA)(H2O)](2-) complex, which suggested that the longer backbone of the multidentate ligand may be pulled tightly into the rst coordination sphere , resulting in high steric constraints at the water binding site.