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Novel Magnetic Resonance Probes

机译：新型磁共振探头

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摘要

The goal of my first project was the synthesis and characterization of novel DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) based ligands with one and two chromophoric tropone coordinating sidearms for the construction of lanthanide based magnetic resonance/optical imaging probes. Lanthanide ions have nearly identical coordination chemistry properties and therefore, the same ligand can be applied to the entire lanthanide series. The development of dual magnetic resonance/optical imaging probes is an exciting current trend in the research area of lanthanide based imaging agents because these probes could combine the high spatial resolution of MRI with the high sensitivity of optical detection. The challenge in the design of these agents is that the requirements for an efficient MR agent (presence of an inner sphere water molecule) are seemingly incompatible with those of optical agents (absence of inner sphere water molecules). Three ligands were synthesized: 1,4,7,10-tetraazacyclododecane-1,4,7-tris(acetic acid)-10-(2-tropone) (1), 1,4,7,10-tetraazacyclododecane-1,7-bis(acetic acid)-4,10-bis(2-tropone), (2) and 1,4,7,10-tetraazacyclododecane-1,4,7-tris(aceticacid)-10-[2-(4-isopropyl)-tropone) (3) Ln3+complexes of these ligands were found to have one inner-sphere water molecule. The r1 relaxivity of Gd 3+ complexes was found to be similar to that of the commercial Gd-based MRI agents. Relaxivity measurements in the presence of human serum albumin (HSA) showed that the Gd3+ complexes weakly bind to HSA. Variable temperature 17O NMR measurements revealed that the neutral O-donor atom of the tropone moiety slows down the water exchange rate of the Gd3+ complexes compared to that for GdDOTA. In vivo MR imaging experiments with Gd1 and Gd3 in mice revealed that the agents were excreted by the kidneys and the liver. The complexes did not show any toxicity at the injected doses (0.1 mmol/kg). The photophysical properties of the Gd3+, Nd3+ and Yb3+ complexes of ligand 1 and 2 were studied by recording the absorption, excitation and emission spectra. The Nd3+ and Yb3+ complexes were found to exhibit bright NIR emission even in aqueous solutions, which indicates that the tropone unit is an efficient sensitizer for these Ln 3+ions. The favorable relaxivity of the Gd3+ complexes and the bright NIR luminescence of the Nd3+ and Yb3+ complexes demonstrate that the tropone chromophore combined with the DOTA framework offers a useful platform for the design of lanthanide-based dual MR/optical imaging agents for in vivo applications.;My second project is related to hyperpolarized 13C magnetic resonance spectroscopy/imaging. The goal of this project was the synthesis of monoethyl [4-13C]-oxaloacetate and its evaluation in dissolution dynamic nuclear polarization NMR experiments as a metabolic probe. Monoethyl [4-13C]-oxaloacetate disodium salt was successfully synthesized. Perfused liver experiments revealed that the compound was taken up by the liver, and metabolized to maleate, citrate and aspartate. Dynamic nuclear polarization to enhance the 13C spin polarization was successfully performed, however, the T1 relaxation time of the 13C label at the C4 position was very short (about 14 s), which precluded its in vivo application as a hyperpolarized 13C metabolic probe.
机译：我的第一个项目的目标是合成和表征新型DOTA（1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸）的配体，该配体具有一个和两个发色托克酮配位侧链，用于构建基于镧系元素的磁共振/光学成像探头。镧系离子具有几乎相同的配位化学性质，因此，可以将相同的配体应用于整个镧系。在基于镧系元素的成像剂的研究领域中，双磁共振/光学成像探针的发展是令人兴奋的当前趋势，因为这些探针可以将MRI的高空间分辨率与光学检测的高灵敏度结合在一起。这些试剂设计的挑战在于，对于有效的MR试剂（存在内球水分子）的要求似乎与光学试剂的要求（不存在内球水分子）不相容。合成了三个配体：1,4,7,10-四氮杂环十二烷-1,4,7-三（乙酸）-10-（2-托酮）（1），1,4,7,10-四氮杂环十二烷-1， 7-双（乙酸）-4,10-双（2-tropone），（2）和1,4,7,10-四氮杂环十二烷-1,4,7-三（乙酸）-10- [2-（ （4-异丙基）-托酮（3）发现这些配体的Ln3 +配合物具有一个内球水分子。发现Gd 3+复合物的r1弛豫性与市售的基于Gd的MRI药剂相似。在人血清白蛋白（HSA）存在下的弛豫度测量表明，Gd3 +复合物与HSA的结合较弱。可变温度的17O NMR测量表明，与GdDOTA相比，托克酮部分的中性O-供体原子减慢了Gd3 +配合物的水交换速率。在小鼠体内对Gd1和Gd3进行的MR体内成像实验表明，这些药物通过肾脏和肝脏排出。在注射剂量（0.1 mmol / kg）下，复合物没有显示出任何毒性。通过记录吸收，激发和发射光谱，研究了配体1和2的Gd3 +，Nd3 +和Yb3 +配合物的光物理性质。发现即使在水溶液中，Nd3 +和Yb3 +配合物也显示出明亮的NIR发射，这表明对于这些Ln 3+离子，托克酮单元是一种有效的敏化剂。 Gd3 +配合物的良好弛豫性以及Nd3 +和Yb3 +配合物的明亮NIR发光表明，托克酮生色团与DOTA框架相结合为体内应用基于镧系元素的双MR /光学成像剂设计提供了有用的平台。 ；我的第二个项目与超极化13C磁共振波谱/成像有关。该项目的目标是合成[4-13C]-草酰乙酸单乙酯，并在溶解动态核极化NMR实验中作为代谢探针对其进行评估。成功合成了[4-13C]-草酰乙酸单乙酯二钠盐。灌注肝脏实验表明该化合物被肝脏吸收，并代谢为马来酸盐，柠檬酸盐和天冬氨酸。成功进行了动态核极化以增强13C自旋极化，但是13C标签在C4位置的T1弛豫时间非常短（约14 s），这使其无法在体内用作超极化13C代谢探针。

著录项

  • 作者

    Hashami, Zohreh.;

  • 作者单位

    The University of Texas at Dallas.;

  • 授予单位 The University of Texas at Dallas.;
  • 学科 Inorganic chemistry.;Biochemistry.;Physical chemistry.
  • 学位 Ph.D.
  • 年度 2018
  • 页码 135 p.
  • 总页数 135
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 康复医学;
  • 关键词

  • 入库时间 2022-08-17 11:53:04

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