Increasing the Utility of Contrast Agents for MRI

该提案的长期目标是解决造影剂领域进展的关键障碍 药物增强磁共振成像（MRI）。我克服这些障碍的计划是增加 镧系元素基造影剂的效用。今后的工作重点将放在造影剂的开发上 用于高场MRI和生理上可行的可活化剂。 指导K99阶段：该提案的博士后阶段（目标1）将根据 教授L。L. Kiessling和R. T.雷恩斯在威斯康星州麦迪逊大学。的 K99阶段的目标是开发使用聚合羟基吡啶酮的高灵敏度MRI试剂 （HOPO）基螯合物。在化学和生物学的接口培训将提供专业知识， 共轭化学，操纵和表征的大分子，和合成新的 镧系元素螯合剂。所获得的知识对于完成目标2-4和 成为一名成功的独立科学家。 独立ROO阶段：在独立阶段（目标2-4），目标2和3重点关注开发 用于MRI的生物反应性造影剂。目标2涉及开发一类新的 使用具有真正零背景状态的树枝状聚合物化学的可活化剂。零背景 增强将能够实现浓度非依赖性成像，克服临床应用的主要障碍。 可活化试剂用于诊断目的的用途。目标3中描述的实验重点是 HOPO基试剂的内球水配位数的调制。新的代理人将 由于水交换的差异， 内层水分子的速率和数量。在目的4中，提供了稳定Eu（II）络合物的方法， 氧化提出。稳定的Eu（II）络合物将在填充空隙的高场强下增强对比度 其中Gd（III）络合物由于长的电子相关时间而不再是可行的造影剂。 相关性：该提案有可能通过促进公共卫生和卫生保健， 通过克服当前的技术限制，增强MRI的诊断能力。拟议的研究可能 导致在治疗通常更有效的最早阶段诊断疾病的能力。

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.