Increasing the Utility of Contrast Agents for MRI

描述(由申请人提供)： 这项提案的长期目标是解决造影剂增强磁共振成像(MRI)领域取得进展的关键障碍。我克服这些障碍的计划是增加基于镧系元素的造影剂的用途。重点将放在高场磁共振造影剂和生理上可行的激活剂的开发上。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的L.L.Kiessling和R.T.Raines教授的指导下进行。K99阶段的目标是开发使用基于聚合物羟基吡啶(HOPO)的螯合物的高度敏感的MRI试剂。这种在化学和生物学的界面上的培训将提供在共轭化学、大分子的操作和表征以及新型稀土螯合剂的合成方面的专业知识。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成功的职业生涯是非常宝贵的。独立Roo阶段：在独立阶段(AIMS 2-4)，AIMS 2和3专注于开发具有生物响应性的MRI造影剂。目标2涉及开发一类使用树枝状大分子化学的新型可激活剂，这些化学物质具有真正的零背景状态。零背景增强将实现不依赖于浓度的成像，克服临床使用可激活试剂用于诊断目的的主要障碍。目标3中描述的实验集中在HOPO基试剂的内球水配位数的调节上。由于水交换速率和内部水分子数量的不同，新的药剂将比类似的聚氨基甲酸酯类药剂具有优势。在目标4中，提出了稳定Eu(11)配合物氧化的方法。稳定的Eu(11)络合物在高场强下将增强对比度，填补Gd(11)络合物由于长的电子相关时间而不再是有效的造影剂的空白。相关性：这项提议有可能通过克服目前的技术限制来提高核磁共振的诊断能力，从而极大地改善公众健康。拟议中的研究可能会导致在治疗往往更有效的早期阶段诊断疾病的能力。

DESCRIPTION (provided by applicant): 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.