Hydroxypyridonate Gd Complexes: MRI Agents

羟基吡啶酮酸钆复合物：MRI 试剂

• 批准号: 7588891
• 负责人: KENNETH N RAYMOND
• 金额: $ 23.84万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7588891
• 关键词: Affect; Anions; Architecture; Behavior; Binding; Biochemical Process; Biological; Blood Circulation; Cations; Charge; Chemistry; Clinical; Collaborations; Complex; Contrast Media; DNA Sequence Rearrangement; Dependence; Dependency; Detection; Development; Diagnostic; Diagnostic radiologic examination; Docking; Electronics; Environment; Equation; Equilibrium; Family; Gadolinium; Gadolinium DTPA; Generations; Goals; Human; Human Development; Image; Image Enhancement; Image Enhancement Agent; Institutes; Ions; Italy; Kinetics; Laboratories; Lanthanoid Series Elements; Lead; Ligands; Magnetic Resonance Imaging; Medicine; Metals; Methods; Modification; Molecular Models; Molecular Weight; Outpatients; Parents; Preparation; Principal Investigator; Process; Progress Reports; Property; Proteins; Protons; Reaction; Relative (related person); Relaxation; Research; Research Personnel; Resolution; Scanning; Series; Serum; Serum Albumin; Site; Solutions; Solvents; Structure; Techniques; Technology; Temperature; Thermodynamics; Time; Tissues; Toxic effect; Universities; Water; Work; alkalinity; analog; aqueous; base; carboxylate; design; frontier; functional group; in vivo; interest; macromolecule; molecular modeling; novel; pressure; programs; research study; scaffold; self assembly; theories

Magnetic resonance imaging (MRI) has provided dramatic new capabilities for diagnostic medicine. MRI enables the acquisition of high resolution, three-dimensional images in the detection of a wide variety of physical abnormalities, and recent advances in dynamic MRI are providing real-time imaging. Over 30% of MRI scans are now acquired using a paramagnetic contrast agent, which enhances the proton relaxation and hence image quality. Gadolinium complexes are most widely used, and these complexes currently are all based on a poly(amino-carboxylate) ligand scaffold . While effective, the relaxivity values (3 - 5mM"V1) of these agents are only a few percent of that theoretically possible, requiring gram amounts of Gd per administration. Attachment of the agent to macromolecules increases the relaxivity by lowering the rotational correlation time, but the rate of water exchange from the gadolinium center then becomes the limiting factor. This project has developed gadolinium complexes (based on a hexadentate hydroxypyridonate ligand scaffold) that are stable and have substantially higher relaxivity due to a water exchange rate at least two orders of magnitude higher than commercial agents. Having developed the agents and demonstrated their stability and fast rates of water exchange, it is now proposed to continue their development for enabling new kinds of imaging. Relaxivities of more than 100mM~1s"1 are the target. This would require much less Gd for images and, more significantly, enable new types of imaging with MRI. Aims include the development of stable agents with 3 (as opposed to the current 1) coordinated water molecules, thus tripling the relaxivity; novel designs of supramolecular Gd clusters; agents that dock to specific targeted biomolecules; and full characterization of those thermodynamic and kinetic properties of these complexes in aqueous solution that are related to their MRI enhancement. The goal is a second generation of MRI agents that utilize relaxivities of up to two orders of magnitude greater than the clinical agents in use today.

磁共振成像 (MRI) 为诊断医学提供了引人注目的新功能。核磁共振成像 能够在检测各种物体时采集高分辨率的三维图像 身体异常以及动态 MRI 的最新进展正在提供实时成像。超过30%的 现在使用顺磁造影剂进行 MRI 扫描，该造影剂可增强质子弛豫 以及图像质量。钆配合物应用最广泛，目前这些配合物 全部基于聚（氨基羧酸）配体支架。虽然有效，但松弛度值 (3 - 5mM"V1) 这些试剂仅是理论上可能的百分之几，每单位需要克量的 Gd 行政。药剂与大分子的附着通过降低旋转来增加弛豫度 相关时间，但来自钆中心的水交换速率则成为限制因素。 该项目开发了钆配合物（基于六齿羟基吡啶酮配体 支架）是稳定的，并且由于水交换率至少为两倍而具有更高的弛豫率 比商业代理高出几个数量级。开发了代理并展示了他们的 稳定性和快速的水交换率，现在建议继续开发它们以实现新的 种成像。目标是弛豫率超过 100mM~1s"1。这需要更少的 Gd 图像，更重要的是，可以通过 MRI 实现新型成像。目标包括发展 具有 3 个（而不是当前的 1 个）配位水分子的稳定剂，从而使弛豫度增加三倍； 超分子 Gd 簇的新颖设计；与特定目标生物分子对接的试剂；和完整的 这些配合物在水溶液中的热力学和动力学性质的表征 与其 MRI 增强有关。目标是利用弛豫度的第二代 MRI 试剂 比当今使用的临床药物高出两个数量级。