NOVEL CONTRAST AGENTS FOR MAGNETIC RESONANCE IMAGING

一系列带有螯合钆的Zyn-连接物分子将被 合成并测试作为新型磁共振造影剂 成像（MRI）。结构变化包括烷基的数量和长度 Zyn-接头的特征链。磁活性结合 人血清白蛋白（HSA）通过相互作用， 在HSA上具有结合位点的烷基“尾”应允许定制血液 池半衰期。将测量HSA结合，并测量摩尔弛豫率。 通过MRI确定的常数。HSA结合应增加摩尔 与单独螯合钆相比的弛豫常数。更高 常数应减少诊断所需的材料量 显像锌连接的钆螯合物的不同释放速率 从HSA应该产生一个家庭的MRI造影剂与广泛的 不同的血池半衰期目前的代理人迅速清除， 血池，需要重复给药和更高的剂量， 长期临床评估。可行性将得到证明，如果 可以鉴定出至少一种化合物， 与Gd-DTPA相比，第二阶段将探讨使用 这些化合物用于血池成像研究，包括短期研究 血管灌注的评估和血管灌注的长期评估 磁导率 拟定商业应用： 1995年MRI研究的市场为4.2亿美元，预计 1999年为7亿美元（医疗保健市场指南）。 原发性高血压、心绞痛及其他类型高血压的研究 缺血性心脏病占约1000万人的60% 1995年进行的MRI研究，条件涉及改变 血管灌注和/或血管渗透性（例如炎症， 肿瘤生长、隐匿性出血）占剩余部分。 所有MRI研究中约30%使用造影剂增强。 这些数字表明，至少有300万例手术使用了MRI， 1995年的造影剂。数量还在增长

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.