通过与磷酸二酯的选择性外壳相互作用激活用于 MRI 的 PARACEST 试剂。
Activation of a PARACEST agent for MRI through selective outersphere interactions with phosphate diesters.
机构信息
Department of Chemistry, University at Buffalo, State University of New York, Buffalo, New York 14260, USA.
出版信息
Inorg Chem. 2010 Jul 5;49(13):5963-70. doi: 10.1021/ic1004616.
Ln(S-THP)(3+) complexes are paramagnetic chemical exchange saturation transfer (PARACEST) agents for magnetic resonance imaging (MRI; S-THP = (1S,4S,7S,10S)-1,4,7,10-tetrakis(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane, Ln(III) = Ce(III), Eu(III), Yb(III)). CEST spectra at 11.7 T show that the PARACEST effect of these complexes is enhanced at neutral pH in buffered solutions containing 100 mM NaCl upon the addition of 1-2 equiv of diethylphosphate (DEP). CEST images of phantoms at 4.7 T confirm that DEP enhances the properties of Yb(S-THP)(3+) as a PARACEST MRI agent in buffered solutions at neutral pH and 100 mM NaCl. Studies using (1)H NMR, direct excitation Eu(III) luminescence spectroscopy, and UV-visible spectroscopy show that DEP is an outersphere ligand. Dissociation constants for Ln(S-THP)(OH(2)) are 1.9 mM and 2.8 mM for Ln(III) = Yb(III) at pH 7.0 and Eu(III) at pH 7.4. Related ligands including phosphorothioic acid, O,O-diethylester, ethyl methylphosphonate, O-(4-nitrophenylphosphoryl)choline, and cyclic 3,5-adenosine monophosphate do not activate PARACEST. BNPP (bis(4-nitrophenyl phosphate) activates PARACEST of Ln(S-THP)(3+) (Ln(III) = Eu(III), Yb(III)), albeit less effectively than does DEP. These data show that binding through second coordination sphere interactions is selective for phosphate diesters with two terminal oxygens and two identical ester groups. A crystal structure of Eu(S-THP)(OH(2))(2)(CF(3)SO(3)) x 2 H(2)O x iPrOH has two outersphere BNPP anions that form hydrogen bonds to the alcohol groups of the macrocycle and the bound water ligand. This structure supports (1)H NMR spectroscopy studies showing that outersphere interactions of the phosphate diester with the alcohol protons modulate the rate of alcohol proton exchange to influence the PARACEST properties of the complex. Further, DEP interacts only with the nonionized form of the complex, Ln(S-THP)(OH(2))(3+) contributing to the pH dependence of the PARACEST effect.
Ln(S-THP)(3+) 配合物是磁共振成像（MRI）的顺磁化学交换饱和转移（PARACEST）试剂；S-THP = (1S,4S,7S,10S)-1,4,7,10-四(2-羟丙基)-1,4,7,10-四氮杂环十二烷，Ln(III) = Ce(III), Eu(III), Yb(III)）。在 11.7 T 下的 CEST 光谱显示，这些配合物的 PARACEST 效应在中性 pH 下在含有 100 mM NaCl 的缓冲溶液中增强，当加入 1-2 当量的二乙基膦酸（DEP）时。在 4.7 T 下的造影剂图像证实，在中性 pH 和 100 mM NaCl 的缓冲溶液中，DEP 增强了 Yb(S-THP)(3+) 作为 PARACEST MRI 试剂的特性。使用（1）H NMR、直接激发 Eu(III) 发光光谱和紫外可见光谱研究表明，DEP 是一种外壳配体。在 pH 7.0 时 Ln(III) = Yb(III)和 pH 7.4 时 Eu(III)，Ln(S-THP)(OH(2))的离解常数为 1.9 mM 和 2.8 mM。相关配体包括硫代磷酸、O,O-二乙酯、乙基甲基膦酸、O-(4-硝基苯膦酰基)胆碱和环状 3,5-腺苷一磷酸均不能激活 PARACEST。BNPP（双（4-硝基苯磷酸）激活 Ln(S-THP)(3+) 的 PARACEST（Ln(III) = Eu(III), Yb(III)），尽管不如 DEP 有效。这些数据表明，通过第二配位球相互作用的结合对具有两个末端氧和两个相同酯基的磷酸二酯具有选择性。Eu(S-THP)(OH(2))(2)(CF(3)SO(3)) x 2 H(2)O x iPrOH 的晶体结构有两个外壳 BNPP 阴离子，它们与大环的醇基团和结合的水配体形成氢键。该结构支持（1）H NMR 光谱研究表明，磷酸二酯与醇质子的外壳相互作用调节醇质子交换的速率，从而影响配合物的 PARACEST 性质。此外，DEP 仅与非电离形式的配合物 Ln(S-THP)(OH(2))(3+) 相互作用，这有助于 PARACEST 效应的 pH 依赖性。
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