Hydroxypyridonate Gd Complexes: MRI Agents

羟基吡啶酮酸钆复合物：MRI 试剂

• 批准号: 7189046
• 负责人: KENNETH N RAYMOND
• 金额: $ 23.21万
• 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/7189046
• 关键词: Affect; Anions; Architecture; Behavior; Binding; Biochemical Process; Biological; Blood Circulation; Cations; Charge; Chemistry; Class; 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 Weight; Numbers; Outpatients; Parents; Preparation; Principal Investigator; Process; Progress Reports; Property; Proteins; Protons; Rate; Reaction; Relative (related person); Relaxation; Research; Research Personnel; Resolution; Scanning; Series; Serum; Serum Albumin; Site; Solutions; Solvents; Structure; Techniques; Technology; Temperature; Thermodynamics; Three-Dimensional Image; Time; Tissues; Today; Toxic effect; Universities; Water; Work; alkalinity; analog; aqueous; base; carboxylate; concept; design; frontier; functional group; in vivo; interest; macromolecule; molecular modeling; novel; pressure; programs; research study; scaffold; self assembly; theories

DESCRIPTION (provided by applicant): 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-1s-1) 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.

描述（由申请人提供）：磁共振成像（MRI）为诊断医学提供了引人注目的新功能。 MRI使得在检测各种物理异常时获得了高分辨率，三维图像，而动态MRI的最新进展正在提供实时成像。现在，使用顺磁对比剂获得了超过30％的MRI扫描，从而增强了质子的松弛并因此，因此图像质量。 Gadolinium复合物是最广泛使用的，这些复合物当前都是基于聚（氨基羧酸盐）配体支架的。虽然有效，但这些药物的松弛度值（3-5mm-1s-1）在理论上可能只有几％，需要每个给药的GD量。通过降低旋转相关时间来增加剂对大分子的附着会提高放松性，但是从Gadolinium中心的水交换速率随后成为限制因素。该项目已经开发了gadolinium复合物（基于六氢羟基甲酸配体支架），由于水汇率至少高两个数量级，因此具有更高的松弛性，其松弛度大大高于商业代理。在开发了代理商并证明了它们的稳定性和快速的水交换速率之后，现在建议继续开发新型成像。超过100mm-1s-1的松弛度是目标。对于图像而言，这将需要更少的GD，更重要的是，可以使用MRI进行新型的成像。目的包括开发3种（与当前1）协调的水分子的稳定药物的发展，从而使松弛性增加了三倍。超分子GD簇的新颖设计；停靠在特定靶向生物分子的代理；以及这些复合物在水溶液中与其MRI增强相关的这些复合物的热力学和动力学特性的全面表征。目标是第二代MRI剂，它利用了比当今使用的临床药物大的宽度大量级数。