Increasing the Utility of Contrast Agents for MRI

这项提案的长期目标是解决在对比领域取得进展的关键障碍。 试剂增强磁共振成像(MRI)。我克服这些障碍的计划是增加 镧系造影剂的应用。重点将放在造影剂的开发上 用于高场磁共振和生理上可行的可激活剂。 指导K99阶段：建议的博士后阶段(目标1)将在 威斯康星大学麦迪逊分校L.L.Kiessling教授和R.T.Raines教授的指导。这个 K99阶段的目标是开发使用聚合物羟基吡哆酸酯的高度敏感的核磁共振成像试剂 (HOPO)基络合物。这项化学和生物相结合的培训将提供以下专业知识 共轭化学、大分子的操纵和表征以及新型化合物的合成 镧系络合剂。所获得的知识将被证明对完成目标2-4和 作为一名独立科学家过渡到一个成功的职业生涯。 独立Roo阶段：在独立阶段(目标2-4)，目标2和3专注于开发 用于核磁共振的生物响应性造影剂。目标2涉及开发一类新的 使用树枝状大分子化学的可激活剂，具有真正的零背景状态。零本底 增强将使不依赖浓度的成像成为可能，克服临床上的主要障碍。 使用可激活的试剂进行诊断。目标3中描述的实验主要集中在 HOPO基试剂内球水配位数的调制。新的代理商将 由于水交换的不同，与类似的聚氨基甲酸酯类试剂相比具有优势 内圈水分子的速率和数量。在目标4中，稳定Eu(11)配合物的方法 提出了氧化的建议。在高场强填充空位时，稳定的Eu(11)络合物将增强对比度 其中，由于较长的电子相关时间，Gd(111)络合物不再是有效的造影剂。 相关性：这项提议有可能通过促进 通过克服目前的技术限制，提高核磁共振的诊断能力。拟议的研究可能 从而能够在治疗往往更有效的最早阶段诊断疾病。

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.