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Increasing the Utility of Contrast Agents for MRI

提高 MRI 造影剂的实用性

基本信息

批准号：
7753605
负责人：
MATTHEW J ALLEN
金额：
$ 24.75万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-01-01 至 2011-12-31
项目状态：
已结题

项目摘要

The long-term goals of this proposal are to address critical barriers to progress in the field of contrast agent-enhanced magnetic resonance imaging (MRI). My plan to overcome these barriers is to increase the utility of lanthanide-based contrast agents. Efforts will be focused on the development of contrast agents for high field MRI and activatable agents that are physiologically viable. Mentored K99 Phase: The postdoctoral phase (aim 1) of the proposal will be carried out under the mentorship of Professors L. L. Kiessling and R. T. Raines at the University of Wisconsin¿Madison. The K99 phase goal is to develop exquisitely sensitive MRI agents using polymeric hydroxypyridonate (HOPO)-based chelates. This training at the interface of chemistry and biology will provide expertise in conjugation chemistries, manipulation and characterization of macromolecules, and the synthesis of novel lanthanide chelators. The acquired knowledge will prove invaluable for completion of aims 2-4 and transition into a successful career as an independent scientist. Independent ROO Phase: In the independent phase (aims 2-4), aims 2 and 3 focus on the development of biologically responsive contrast agents for MRI. Aim 2 involves the development of a novel class of activatable agents using dendrimer chemistry that have a true zero-background state. Zero background enhancement would enable concentration-independent imaging, overcoming a major barrier to the clinical use of activatable agents for diagnostic purposes. The experiments described in aim 3 focus on modulation of the innersphere water coordination number of HOPO-based agents. The new agents will have advantages over similar poly(aminocarboxylate)-based agents due to differences in water exchange rate and number of innersphere water molecules. In aim 4, methods to stabilize Eu(ll) complexes from oxidation are proposed. Stable Eu(ll) complexes will enhance contrast at high field strengths filling the void where Gd(lll) complexes cease to be viable contrast agents because of long electronic correlation times. Relevance: This proposal has the potential to greatly improve public health through advancement of the diagnostic capabilities of MRI by overcoming current technological limitations. The proposed research may lead to the ability to diagnose diseases at the earliest stages where treatments are often more effective.

该提案的长期目标是解决对比度领域取得进展的关键障碍药剂增强磁共振成像（MRI）。我克服这些障碍的计划是增加镧系造影剂的实用性。将重点致力于造影剂的开发用于高场 MRI 和生理上可行的可激活剂。指导K99阶段：该提案的博士后阶段（目标1）将在威斯康星大学麦迪逊分校 L. L. Kiessling 和 R. T. Raines 教授的指导。这 K99 阶段的目标是使用聚合羟基吡啶酮盐开发极其灵敏的 MRI 试剂 (HOPO) 基螯合物。这种化学和生物学交叉的培训将提供以下方面的专业知识：共轭化学、大分子的操作和表征以及新型化合物的合成镧系元素螯合剂。所获得的知识对于完成目标 2-4 和作为一名独立科学家过渡到成功的职业生涯。独立原产地组织阶段：在独立阶段（目标2-4），目标2和3侧重于发展用于 MRI 的生物响应造影剂。目标 2 涉及开发一类新颖的使用树枝状聚合物化学的可激活试剂具有真正的零背景状态。零背景增强将实现浓度无关成像，克服临床的主要障碍使用可激活剂进行诊断。目标 3 中描述的实验侧重于基于 HOPO 的试剂内层水配位数的调节。新的代理将由于水交换的差异，与类似的基于聚（氨基羧酸盐）的试剂相比具有优势内层水分子的速率和数量。在目标 4 中，稳定 Eu(II) 配合物的方法建议氧化。稳定的 Eu(II) 配合物将增强填充空隙的高场强对比度其中，由于电子相关时间较长，Gd(III) 复合物不再是可行的造影剂。相关性：该提案有可能通过推进 MRI 的诊断能力克服了当前的技术限制。拟议的研究可能导致能够在最早阶段诊断疾病，而治疗往往更有效。