NEW CONCEPTS IN MRI CONTRAST AGENT DESIGNS

MRI 造影剂设计的新概念

• 批准号: 6134061
• 负责人: Peter A Petillo
• 金额: $ 1.15万
• 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/6134061
• 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（改编自申请人摘要）：概念新颖的MRI 顺磁性造影剂（PCA）将被合成，这是第一个 时间将同时提供增强的弛豫性、 金属离子，降低毒性，溶液动力学光谱探针， 代谢敏感的氧化还原开关。 前提是， 氮氧化物-金属相互作用将增加 Gd（III）-PCA通过提供额外的导管来转移磁性 金属的瞬间溶解水。 两个新提出的类别 螯合物通过引入刚性氮氧化合物而超越了当前的设计范例， 将这些部分引入到明确定义的三维支架中， 相对于金属中心的氮氧化合物。 这种策略创造了运动 灵敏的探头，内部节段或各向异性运动不复杂 并且将允许直接确定旋转相关性 时间和其他解旋转动力学观测。 因此，水 通过提供额外的服务， 互动模式 每个新的PCA将经受可变温度 多频CW EPR研究和完整的线型分析，以揭示其 解决方案动态。 此外，激光荧光动力学实验 将进行这些观测弛豫提供额外的数据。 最后，将评价每种化合物的体外毒性。 独特的 这些试剂的分子特性将提供更好的理解， 在临床中增加PCA有效性的结构特征 设置. 这些试剂，由于其对体内的潜在敏感性， 氧气浓度，将允许代谢的发展 增强MRI对缺氧敏感性的反应剂，并提供更多 易于应用的诊断特异性用于缺血性疾病的试剂。 的 我们的计划是开发小而有区别的PCA。 络合物形成 先进材料发展的结构起点， 更高的效力，更低的毒性和更好的诊断特异性，包括 靶向特定组织和病理。