NOVEL CONTRAST AGENTS FOR MAGNETIC RESONANCE IMAGING

一系列带有螯合Gd的Zyn-Linker分子将 新型磁共振造影剂的合成与测试 成像(MRI)。结构变化包括烷基的数目和长度 ZYN-接头特有的链。磁活性结合 小分子与人血清白蛋白的相互作用 在HSA上有结合部位的烷基“尾巴”应该允许剪裁血液 泳池的半衰期。将测量人血清白蛋白结合和摩尔松弛系数 由核磁共振确定的常数。人血清白蛋白结合应增加摩尔分数 弛豫常数与单独的螯合Gd相比较。一个更高的 常量应减少诊断所需的材料量 成像。不同释放速率的锌键合Gd络合物 应该生产一系列具有广泛应用价值的磁共振造影剂 不同的血池半衰期。目前的特工很快就被清除了 血池，需要重复给药和更高剂量的治疗 延长了临床评估时间。如果在以下情况下，将论证可行性 至少可以确定一种化合物，其中&gt； 弛豫度与Gd-DTPA的比较。阶段Il将探索使用 这些化合物用于血池成像研究，包括短期 血管灌注的评估和血管的长期评估 渗透性。 建议的商业应用： 核磁共振研究的市场在1995年为4.2亿美元，预计将 1999年将达到7亿美元(《医疗保健市场指南》)。 高血压、心绞痛及其他形式心绞痛的研究 在约1000万人中，缺血性心脏病占60% 1995年进行的核磁共振研究，条件涉及改变 血管灌流和/或血管渗透性(例如炎症， 肿瘤生长、隐匿性出血)占其余部分。 大约30%的MRI研究是用造影剂增强的。 这些数字表明，至少有300万例手术使用了核磁共振 造影剂于1995年推出。这一数字正在增长。

A series of Zyn-Linker molecules bearing chelated gadolinium will be synthesized and tested as novel contrast agents for magnetic resonance imaging (MRI). Structural variations include number and length of alkyl chains Characteristic of Zyn-Linkers. Binding of magnetically active small molecules to human serum albumin (HSA) through interaction of alkyl "tails" with binding sites on HSA should allow tailoring of blood pool half-lives. HSA binding will be measured and molar relaxivity constants determined by MRI. HSA binding should increase molar relaxivity constants compared to chelated gadolinium alone. A higher constant should reduce the amount of material required for diagnostic imaging. Different rates of release of Zyn-Linked Gadolinium chelates from HSA should produce a family of MRI contrast agents with widely varying blood pool half-lives. Current agents are rapidly cleared from the blood pool and require repeat administration and higher doses for prolonged clinical evaluation. Feasibility will be demonstrated if at least one compound can be identified which exhibits >5x increase in relaxivity compared with Gd-DTPA. Phase Il will explore the uses of these compounds for blood pool imaging studies including short term assessment of vascular perfusion and longer term assessment of vascular permeability. PROPOSED COMMERCIAL APPLICATION: The market for MRI studies was $420 million in 1995 and is projected to be $700 million in 1999 (Medical & Healthcare Market-place Guide). Studies on essential hypertensIon, angina pectorIs and other forms of Ischemic heart disease accounted for 60% of the approximately 10 million MRI studies performed In 1995, with conditions Involving altered vascular perfusion and/or vascular permeability (e.g. inflammation, tumor growth, occult bleeding) accounting for the remainder . Approximately 30% of all MRI studies were enhanced with contrast agents. These figures suggest that at least 3 million procedures used MRI contrast agents in 1995. that the numbers are growing.