Synthesis and Physicochemical Characterization of Carbon Backbone Modified [Gd(TTDA)(H2O)]2鈭?/sup> Derivatives

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• 作者：Ya-Hui Chang ; Chiao-Yun Chen ; Gyan Singh ; Hsing-Yin Chen ; Gin-Chung Liu ; Yih-Gang Goan ; Silvio Aime ; Yun-Ming Wang
• 刊名：Inorganic Chemistry
• 出版年：2011
• 出版时间：February 21, 2011
• 年：2011
• 卷：50
• 期：4
• 页码：1275-1287
• 全文大小：1034K
• 年卷期：v.50,no.4(February 21, 2011)
• ISSN：1520-510X

文摘

The present study was designed to exploit optimum lipophilicity and high water-exchange rate (k_ex) on low molecular weight Gd(III) complexs to generate high bound relaxivity (r₁^b), upon binding to the lipophilic site of human serum albumin (HSA). Two new carbon backbone modified TTDA (3,6,10-tri(carboxymethyl)-3,6,10-triazadodecanedioic acid) derivatives, CB-TTDA and Bz-CB-TTDA, were synthesized. The complexes [Gd(CB-TTDA)(H₂O)]^{2鈭?/sup> and [Gd(Bz-CB-TTDA)(H₂O)]2鈭?/sup> both display high stability constant (log K_GdL = 20.28 and 20.09, respectively). Furthermore, CB-TTDA (log K_(Gd/Zn) = 4.22) and Bz-CB-TTDA (log K_(Gd/Zn) = 4.12) exhibit superior selectivity of Gd(III) against Zn(II) than those of TTDA (log K_(Gd/Zn) = 2.93), EPTPA-bz-NO₂ (log K_(Gd/Zn) = 3.19), and DTPA (log K_(Gd/Zn) = 3.76). However, the stability constant values of [Gd(CB-TTDA)(H₂O)]2鈭?/sup> and [Gd(Bz-CB-TTDA)(H₂O)]2鈭?/sup> are lower than that of MS-325. The parameters that affect proton relaxivity have been determined in a combined variable temperature 17O NMR and NMRD study. The water exchange rates are comparable for the two complexes, 232 脳 106 s鈭? for [Gd(CB-TTDA)(H₂O)]2鈭?/sup> and 271 脳 106 s鈭? for [Gd(Bz-CB-TTDA)(H₂O)]2鈭?/sup>. They are higher than those of [Gd(TTDA)(H₂O)]2鈭?/sup> (146 脳 106 s鈭?), [Gd(DTPA)(H₂O)]2鈭?/sup> (4.1 脳 106 s鈭?), and MS-325 (6.1 脳 106 s鈭?). Elevated stability and water exchange rate indicate that the presence of cyclobutyl on the carbon backbone imparts rigidity and steric constraint to [Gd(CB-TTDA)(H₂O)]2鈭?/sup>and [Gd(Bz-CB-TTDA)(H₂O)]2鈭?/sup>. In addition, the major objective for selecting the cyclobutyl is to tune the lipophilicity of [Gd(Bz-CB-TTDA)(H₂O)]2鈭?/sup>. The binding affinity of [Gd(Bz-CB-TTDA)(H₂O)]2鈭?/sup> to HSA was evaluated by ultrafiltration study across a membrane with a 30 kDa MW cutoff, and the first three stepwise binding constants were determined by fitting the data to a stoichiometric model. The binding association constants (K_A) for [Gd(CB-TTDA)(H₂O)]2- and [Gd(Bz-CB-TTDA)(H₂O)]2- are 1.1 脳 102 and 1.5 脳 103, respectively. Although the K_A value for [Gd(Bz-CB-TTDA)(H₂O)]2- is lower than that of MS-325 (K_A = 3.0 脳 104), the r₁b value, r₁b = 66.7 mM鈭? s鈭? for [Gd(Bz-CB-TTDA)(H₂O)]2-, is significantly higher than that of MS-325 (r₁b = 47.0 mM鈭? s鈭?). As measured by the Zn(II) transmetalation process, the kinetic stabilities of [Gd(CB-TTDA)(H₂O)]2鈭?/sup>, [Gd(Bz-CB-TTDA)(H₂O)]2鈭?/sup>, and [Gd(DTPA)(H₂O)]2鈭?/sup> are similar and are significantly higher than that of [Gd(DTPA-BMA)(H₂O)]2鈭?/sup>. High thermodynamic and kinetic stability and optimized lipophilicity of [Gd(CB-TTDA)(H₂O)]2鈭?/sup> make it a favorable blood pool contrast agent for MRI.}