CB-TTDA及TTDA-胜肽及其金屬錯合物之合成、物性及化性研究

Synthesis and Physicochemical Characterization of CB-TTDA and TTDA-peptide conjugate and Their Metal Complexes

邱芝瑋(Chih-Wei Chiu)

指導教授 ： 王雲銘

高雄醫學大學/生命科學院/醫藥暨應用化學研究所/碩士(2005年)

摘要

本研究主要為合成含環丁基之TTDA(3,6,10-tri(carboxymethyl)- 3,6,10- triazadodecanedioic acid)衍生物，CB-TTDA(8-cyclobutyl- 3,6,10-tri-(carboxymethyl)-3,6,10-triazadodecanedioic acid)。利用電位滴定法求得配位子的總鹼度（?櫝Ka）為28.59，與釓金屬形成錯合物的穩定常數為21.29。釓金屬錯合物弛緩率（r1）與pH值及溫度間關係乃利用20 MHz relaxometer進行研究，在37℃，pH 7.4狀態下具弛緩率（r1）為4.12mM-1s-1。此外，由鏑金屬錯合物在pH 6.30中17O-NMR化學位移之變化可求出內層水分子數（q）為1。釓金屬錯合物的弛緩率（r1）受到內層水分子的存在時間 (τm)及分子轉動相關時間(?酺)的影響。研究結果顯示[Gd(CB-TTDA)]2?{的內層水分子存在時間（τm）為4.3ns，較[Gd(TTDA)]2?{（τm＝6.8 ns）短。另外，實驗結果亦發現，[Gd(CB-TTDA)]2?{之分子轉動時間﹙?酺﹚為112 ps，大於[Gd(TTDA)]2?{（?酺＝104 ps）。利用兩種不同脂溶性配位子TTDA與(S)-4-Bz-TTDA ((S)-4-benzyl-3,6,10-tri(carboxymethyl)-3,6,10-triazadodecanedioic acid)為架構，將其與胜肽結合，發展具生物活性釓金屬錯合物。[Gd(TTDA)]2?{在37 ?aC、pH 7.4狀態下其弛緩率（r1）為3.89 mM-1s-1，接上胜肽後其弛緩率增加為7.01 mM-1s-1，而[Gd((S)-4-Bz-TTDA)]2?{在37 ?aC、pH 7.4狀態下其弛緩率（r1）為4.9 mM-1s-1，接上胜肽後其弛緩率增加為7.74 mM-1s-1。此外與酵素反應後，具有脂溶性官能基之釓金屬錯合物[Gd((S)-4-Bz-TTDA)]2?{，能與HSA產生鍵結，弛緩率提高為12.73 mM-1s-1。

關鍵字

核磁共振造影

並列摘要

A derivative of TTDA (3,6,10-tri(carboxymethyl)-3,6,10- triazadodecanedioic acid), CB-TTDA(8-cyclobutyl-3,6,10-tri-(carboxy methyl)-3,6,10-triazadodecanedioic acid), was synthesized. 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 ligand for Gd3+ over endogenously available metal ions were investigated. The observed longitudinal relaxivity (r1) of [Gd(CB-TTDA)]2?{ was 4.12 mM-1s-1 at 37 ?aC. The 17O NMR longitudinal and transverse relaxation rates and chemical shifts were thoroughly investigated in order to study water-exchange rate (Kex298) value?|?nResidence lifetime of bound water (?鄝) obtained from [Gd(CB-TTDA)]2?{ is shorter than that of [Gd(TTDA)]2?{. The rotational correlation time (?酺) for [Gd(CB-TTDA)]2?{ (?酺＝112 ps ) is also longer than that of [Gd(TTDA)]2?{ (?酺＝103 ps). The bioactivity Gd3+ complexes were synthesized by conjugated the different lipophilicity of ligands, TTDA and (S)-4-Bz-TTDA ((S)-4-benzyl-3,6,10-tri(carboxy methyl)-3,6,10- triazadodecanedioic acid) bound with peptide. The observed longitudinal relaxivity (r1) of [Gd(TTDA)]2?{ and [Gd((S)-4-Bz-TTDA)]2?{, at 37 ?aC were 3.89 mM-1s-1 and 4.9 mM-1s-1, respectively. The observed longitudinal relaxivity (r1) of [Gd(TTDA)]2?{ and [Gd((S)-4-Bz-TTDA)]2?{ conjugated with peptide, at 37 ?aC was 7.01 mM-1s-1 and 7.74 mM-1s-1, respectively. The lysine residues are to be the good substrates for cleavage by TAFI (thrombin-activatable fibrinolysis inhibitor, human carboxypeptidase B). The [Gd((S)-4-Bz-TTDA)]2?{ bound well to HSA and enhanced the complex’s relaxivity(r1) conjugated with peptide.

並列關鍵字

MRI

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