NEW CONCEPTS IN MRI CONTRAST AGENT DESIGNS

MRI 造影剂设计的新概念

• 批准号: 2519995
• 负责人: Peter A Petillo
• 金额: $ 13.44万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 2002-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2519995
• 关键词: chelating agents; chemical structure function; chemical synthesis; contrast media; electron spin resonance spectroscopy; gadolinium; magnetic resonance imaging; metal complex; molecular dynamics

DESCRIPTION (Adapted from Applicant's Abstract): Conceptually novel MRI paramagnetic contrast agents (PCAs) will be synthesized, which for the first time will simultaneously provide enhanced relaxivity, encapsulation of the metal ion, reduced toxicity, spectroscopic probes of solution dynamics, and metabolically sensitive redox switches. The premise is that enforced nitroxide-metal interactions will increase the native relaxivities of Gd(III)-PCAs by providing an additional conduit to transfer the magnetic moment of the metal to solvating water. The two new proposed classes of chelates go beyond current design paradigms by incorporating rigid nitroxide moieties into well-defined 3-dimensional scaffolds that fix the position of the nitroxide relative to the metal center. This strategy creates motion sensitive probes uncomplicated by internal segmental or anisotropic motions and will allow for the direct determination of the rotational correlation time and other solution rotational dynamical observables. Thus, the water exchange properties of PCAs will be better managed by providing additional interaction modes. Each new PCA will be subjected to variable temperature multifrequency CW EPR studies and complete lineshape analysis to reveal its solution dynamics. In addition, laser fluorescence dynamics experiments will be performed to provide additional data on these observed relaxivities. Finally, each compound will be evaluated for in vitro toxicity. The unique molecular properties of these agents will deliver a better understanding of the structural features that increase PCA effectiveness in a clinical setting. These agents, by virtue of their potential sensitivity to in vivo oxygen concentrations, will allow for the development of metabolically responsive agents with enhanced MRI sensitivity to hypoxia and provide more easily applied agents diagnostically specific for ischemic disorders. The plan is to develop small, yet discriminating PCAs. The complexes form the structural starting point for the development of advanced materials with higher potency, lower toxicity, and better diagnostic specificity, including targeting of specific tissues and pathologies.

描述(改编自申请者摘要)：概念新颖的磁共振成像 将合成顺磁性造影剂(PCA)，这是第一次 时间将同时提供增强的松弛，封装 金属离子，降低毒性，溶液动力学的光谱探测器，以及 代谢敏感的氧化还原开关。前提是强制执行 氮氧化物-金属相互作用将增加自然弛豫度 Gd(III)-PCAs通过提供额外的管道来转移磁性 金属对溶解水的力矩。建议开设的两个新班级 通过加入刚性氮氧化物，络合物超越了当前的设计范例 部分进入定义良好的三维支架，该支架固定 相对于金属中心的氮氧化物。这一战略创造了动感 不受内部节段性或各向异性运动影响的敏感探头 并将允许直接确定旋转相关性 时间和其他解的转动动力学观测值。因此，水 PCA的交换属性将通过提供更多 交互模式。每个新的主成分分析都将受到可变温度的影响 多频连续波EPR研究和完整的线形分析以揭示其 溶液动力学。此外，还进行了激光荧光动力学实验 将被执行以提供关于这些观察到的弛豫度的额外数据。 最后，将对每种化合物进行体外毒性评估。独一无二的 这些试剂的分子性质将使我们更好地理解 提高临床自控镇痛有效性的结构特征 布景。这些药物，凭借其对体内的潜在敏感性 氧气浓度，将允许新陈代谢发展 具有增强的MRI对低氧敏感性的响应剂，并提供更多 易于应用的药物，专用于诊断缺血性疾病。这个 计划是发展规模较小、但具有区分性的PCA。这些复合体形成了 发展先进材料的结构起点 更高的效力、更低的毒性和更好的诊断特异性，包括 以特定组织和病理为靶点。