| Summary: | 博士 === 高雄醫學大學 === 藥學研究所博士班 === 95 === Two novel derivatives of TTDA (3,6,10-tri(carboxymethyl)-3,6,10- triazadodecanedioic acid), TTDA-BOM and TTDA-N''-BOM, which have a benzyloxymethyl group, were synthesized. Moreover, one monoamide and two bis(amide) derivatives of TTDA, TTDA-N-MOBA, TTDA-BMA and TTDA-BBA, were synthesized. The values of the stability constant of Gd(III) complexes with TTDA-mono- and bis(amide) are significantly lower than those of [Gd(TTDA)]2?{ and [Gd(DTPA)]2?{, but the selectivity constants of these ligands for Gd(III) over Zn(II) and Cu(II) are slightly higher than those of TTDA and DTPA. On the other hand, as measured by the Zn(II) transmetallation process, the kinetic stability of [Gd(TTDA-BOM)]2?{ and [Gd(TTDA-N''-BOM)]2?{ is significantly higher than that of [Gd(DTPA-BMA)]. In addition, the relaxivity (r1) values of [Gd(TTDA-BOM)]2?{, [Gd(TTDA-N''-BOM)]2?{, [Gd(TTDA-MOBA)]?{, [Gd(TTDA-BMA)] and [Gd(TTDA-BBA)] using 20 MHz relaxometer at 37.0 ?b 0.1 ?aC were 4.42, 4.44, 4.23, 3.92 and 4.41 mM?{1 s?{1, respectively. 17O NMR longitudinal and transverse relaxation rates and chemical shifts were measured at variable temperature at 9.4 T magnetic fields for aqueous solutions of these Gd(III) complexes. The water exchange rate (kex298) values for [Gd(TTDA-BOM)]2− (117 ?e 106 s?{1) and [Gd(TTDA- N''-BOM)]2?{ (131 ?e 106 s?{1) are significantly higher than those of [Gd(DTPA)]2− (4.1 ?e 106 s?{1) and [Gd(BOPTA)]2− (3.45 ?e 106 s?{1), and are similar to that of [Gd(TTDA)]2− (146 ?e 106 s?{1). For the TTDA-monoamide, [Gd(TTDA-MOBA)]?{, the kex298 value is 29.1 ?e 106 s?{1, about one-fifth of the water exchange rate on [Gd(TTDA)]2−. Furthermore, for the TTDA-bis(amide), [Gd(TTDA-BMA)] and [Gd(TTDA-BBA)], the kex298 values are 15.2 ?e 106 s?{1 and 15.6 ?e 106 s?{1, respectively, about one-tenth of the water exchange rate on [Gd(TTDA)]2−. The rotational correlation time (?豩) values for [Gd(TTDA-BOM)]2− (119 ps), [Gd(TTDA-N''-BOM)]2?{ (125 ps), [Gd(TTDA-MOBA)]?{ (157 ps), [Gd(TTDA-BMA)] (119 ps) and [Gd(TTDA-BBA)] (187 ps) are higher than those of [Gd(DTPA)]2− (103 ps) and [Gd(TTDA)]2− (104 ps). Fluorescent probe displacement studies exhibit that [Gd(TTDA-BOM)]2– and [Gd(TTDA-N''-BOM)]2– can displace dansylsarcosine from HSA with inhibition constants (Ki) of 1900 ?嵱 and 1600 ?嵱, respectively; however, they are not able to displace warfarin. These results indicate that [Gd(TTDA-BOM)]2– and [Gd(TTDA-N''-BOM)]2– have a weak binding to subdomain IIIA on HSA. In addition, binding constant (KA) values for [Gd(TTDA-BOM)]2?{/HSA, [Gd(TTDA-N’-BOM)]2?{/HSA and [Gd(TTDA-BBA)]/HSA are 4.6 ?e 102, 5.4 ?e 102 and 1.0 ?e 104 M?{1, respectively; and bound relaxivity ( ) values are 65.8, 61.5 and 52.0 mM?{1 s?{1, respectively. Finally, from the relaxivity and ultrafiltration studies, it is clear that the bound relaxivity (r1b) values of [Gd(TTDA-BOM)]2–, [Gd(TTDA-N''-BOM)]2– and [Gd(TTDA-BBA)] are higher than that of MS-325 which is commercial MRI contrast agent.
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