| Summary: | 博士 === 高雄醫學大學 === 藥學研究所 === 90 === This report herein describes the synthesis of eight derivatives of DTPA（3,6,9-tri(carboxymethyl)-3,6,9-triazadodecanedioic acid）and TTDA（3,6,10-tri(carboxymethyl)-3,6,10-triazadodecanedioic acid） derivatives, N’-pyridylmethyl (DTPA-PY，TTDA-PY), N’-2-hydroxypropyl (DTPA-HP，TTDA-HP), N’-2-hydroxy-1-phenylethyl (DTPA-H1P，TTDA-H1P) and N’-2-hydroxy-2-phenylethyl (DTPA-H2P，TTDA-H2P). The ligand protonation constants, thermodynamic stability constants, conditional stability constants of Gd3+, Cu2+, Zn2+ and Ca2+ complexes, the selectivity constants and modified selectivity constants of the ligands for Gd3+ over endogenously available metal ions were investigated. 1H NMR and 2D COSY spectra shown that the oxygen atom of the hydroxy group is not coordinated to metal ion in [La(TTDA-HP)] complex. The observed longitudinal relaxivity (r1) of [Gd(DTPA-PY)], [Gd(DTPA-HP)], [Gd(DTPA-H1P)]—, [Gd(DTPA-H2P)]—, [Gd(TTDA-PY)], [Gd(TTDA-HP)], [Gd(TTDA-H1P)]— and [Gd(TTDA-H2P)]— at 37 C were of 4.43, 6.52, 5.67, 6.14, 3.905.53, 5.28 and 4.94 mM-1 s-1, respectively. 17O NMR chemical shifts showed that [Dy(DTPA-PY)], [Dy(DTPA-HP)], [Dy(DTPA-H1P)], [Dy(DTPA-H2P)], [Dy(TTDA-PY)], [Dy(TTDA-HP)], [Dy(TTDA-H1P)] and [Dy(TTDA-H2P)] complexes at pH 6.30 had 1.3, 2.1, 1.9, 2.2, 0.9, 2.2, 2.0 and 1.8 inner-sphere water molecules, respectively. The EPR transverse electronic relaxation rate and 17O NMR transverse relaxation time were thoroughly investigated in order to study water-exchange rates Short exchange lifetime values were obtained for [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. To use the advantage characteristic of the fast water-exchange rate of [Gd(TTDA-PY)], [Gd(TTDA-PY)]/HSA adduct was synthesized in order to enhance the relaxivity. However, the binding constant (KA) of [Gd(TTDA-PY)]/HSA adduct was less than 100 M-1. Therefore, the significant increase of the relaxivity of [Gd(TTDA-PY)]/HSA adduct was not observed. On the other hand, the usage of the characteristic of the fast water-exchange rate of [Gd(TTDA)]2 derivatives, TTDA and protamine was conjugated using squarate as a linker. The relaxivity value of Gd(TTDA-SQ)5-pro19 is of 18.2 mM-1 s-1 which is significantly higher than that of Gd(DO3ASQ)3-lys16 (15.6 mM-1 s-1). The temperature dependence of the relaxivity for the Gd(TTDA-SQ)5-pro19 complex at 20 MHz shown that a monoexponential decrease of the observed relaxivity upon increasing the temperature was observed and this was the characteristic of the fast water-exchange rate for Gd(TTDA-SQ)5-pro19 conjugate.
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