Bz-CB-TTDA與NB-CB-TTDA配位子及其釓金屬錯合物之合成及物化特性研究

Synthesis and Physicochemical Characterization of Bz-CB-TTDA, NB-CB-TTDA and their Gd(III) Complexes

張雅惠(Ya-Hui Chang)

指導教授 ： 陳信允

高雄醫學大學/生命科學院/醫藥暨應用化學研究所/碩士(2009年)

摘要

本研究設計與合成出兩個新穎的配位子，Bz-CB-TTDA(4-benzyl-8-cyclobutyl-3,6,10-tri-(carboxymethyl)-3,6,10- triazadodecanedioic acid)及NB-CB-TTDA(8-cyclobutyl-3,6,10-tri- (carboxymethyl)-4-p-nitrobenzyl-3,6,10-triazadodecanedioic acid)。Bz-CB-TTDA及 NB-CB-TTDA之釓金屬錯合物在20 MHz、37.0 ± 0.1 °C下，求得其弛緩率（r1）分別為4.29及4.28 mM−1s−1。利用螢光光譜儀測定[Eu(Bz-CB-TTDA)]2−與[Eu(NB-CB-TTDA)]2−錯合物，求出其內層水分子數(q)分別為1.26 (1.44)及1.31 (1.20)。釓金屬錯合物之內層水分子交換速率（kex298）及分子轉動相關時間（τR）則利用9.4 T之17O NMR求得。研究結果顯示 [Gd(Bz-CB-TTDA)]2−與[Gd(NB-CB-TTDA)]2−的水交換速率271及268 × 106 s−1較[Gd(TTDA)]2−快，且與[Gd(CB-TTDA)]2−相近。另外， [Gd(Bz-CB-TTDA)]2−與[Gd(NB-CB-TTDA)]2−之分子轉動時間(τr)相似分別為151及147 ps，大於[Gd(DTPA)]2− (τr = 103 ps)及[Gd(TTDA)]2− (τr = 104 ps)。而在動力學穩定度探討中發現，[Gd(Bz-CB-TTDA)]2−明顯比[Gd(DTPA-BMA)]穩定。在[Gd(Bz-CB-TTDA)]2–與HSA形成非共價性鍵結實驗中，分別求得鍵結常數（KA）為1.7 × 103 M−1，與超過濾實驗結果相似(1.3 ×103 M−1)，而鍵結弛緩率（r1b）為66.7 mM−1s−1高於磁振造影對比劑MS-325。

關鍵字

磁振造影對比劑 ； 熱力學穩定度 ； 弛緩率 ； 釓金屬錯合物

並列摘要

Two novel derivatives of CB-TTDA (8-cyclobutyl- 3,6,10-tri-(carboxymethyl)-3,6,10-triazadodecanedioic acid), Bz-CB- TTDA (4-benzyl-8-cyclobutyl-3,6,10-tri-(carboxymethyl)-3,6,10-triaza dodecanedioic acid) and NB-CB-TTDA (8-cyclobutyl-3,6,10-tri- (carboxymethyl)-4-p-nitrobenzyl-3,6,10-triazadodecanedioic acid) were designed and synthesized. The relaxivity (r1) values of [Gd(Bz-CB-TTDA)]2− and [Gd(NB-CB-TTDA)]2− using 20 MHz relaxometer at 37.0 ± 0.1 °C were 4.29 and 4.28 mM−1s−1, respectively. The number of inner-sphere water (q ≈ 1) of [Eu(Bz-CB-TTDA)]2− and [Eu(NB-CB-TTDA)]2− was obtained by chemical-luminescence method. 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(Bz-CB-TTDA)]2− (271 × 106 s−1) and [Gd(NB-CB- TTDA)]2− (268 × 106 s−1) are significantly higher than that of [Gd(TTDA)]2− (146 × 106 s−1) and are similar to that of [Gd(CB-TTDA)]2− (232 × 106 s−1). The rotational correlation time (τR) values for [Gd(Bz-CB-TTDA)] (151 ps) and [Gd(NB-CB- TTDA)] (147 ps) are higher than those of [Gd(TTDA)]2− (104 ps) and [Gd(CB-TTDA)]2− (112 ps). Then, as measured by the Zn(II)
transmetallation process, the kinetic stability of [Gd(Bz-CB-TTDA)]2− is significantly higher than that of [Gd(DTPA-BMA)]. In addition, binding constant (KA) value for [Gd(Bz-CB-TTDA)]2−/HSA is 1.7 × 103 M−1 which is similar to the results from ultrafiltration studies; and bound relaxivity (r1b) value 66.7 mM−1s−1 is higher than that of MS-325.

並列關鍵字

Magnetic resonance imaging ； Contrast agent ； Thermodynamic stability ； Kinetic ； Relaxivity ； Gadolinium complex

參考文獻

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