Targetable Exploratory Multinuclear MRI Contrast Agents

描述(申请人提供)：磁共振成像(MRI)是一种非常有用的诊断成像方法，它以高空间分辨率而闻名，它可以在不使用放射性核素的情况下提供临床医生所需的图像。使用Gd(III)离子作为一种可注射的无毒DOTA螯合物，通过增加与Gd(III)离子造影剂相关的水分子中质子的核自旋弛豫速率来增强MRI信号，Gd(III)离子造影剂本身具有7个未配对的电子。磁共振现象的另一个新兴生物医学应用是使用顺磁性Gd(III)造影剂作为重要分子或癌细胞的标记，其位置可以通过磁共振造影剂响应(分子成像)进行空间跟踪。分子成像对于了解造影剂标记的分子或细胞如何在活体动物中传播以及疾病的最终治疗非常重要。分子成像过程可以显著提高效率。如果多核Gd(III)物种可以通过将几个Gd(III)中心连接到中心分子收集点并由此产生的阵列结合到一个大的寻找癌症的抗体分子上来制造，该抗体分子将针对要成像的癌症，那么MRI过程的效率将会提高。国家癌症研究所的这项R21探索/开发基金的目标是对具有上述特征的潜在有价值的磁共振造影剂新家族的成员进行探索性合成和评估。在结构上，这些建议的试剂由一个中心收集物种组成，该物种由一个非常稳定的二十面体B12(-2)笼子组成。这个B12(-2)笼子的每个顶点，除了一个外，都可以共价结合到携带DOTA螯合Gd(III)中心的有机连接物臂上。因此，11个Gd(111)造影剂中心可以连接到单个B12(-2)核心，然后该核心连接到能够选择性地与癌细胞结合的生物分子，以提供分子成像。11个Gd(111)MR对比剂中心的存在增强了每个抗体分子产生的观察信号，从而提高了方法的灵敏度。研究将涉及这些新造影剂结构(闭合体)的化学合成，通过最小化Gd(111)螯合物基团的分子内运动来提高性能的新方法的探索，以及允许附着生物分子分子靶向癌症的结构的开发。

DESCRIPTION (provided by applicant): Magnetic Resonance Imaging (MRI) is an extraordinarily useful method for diagnostic imaging and it is noted for the high spatial resolution it can provide to images needed by clinical physicians without the use of radionuclides. The use of gadolinium (III) ion as an injectable non-toxic DOTA chelate intensifies the MRI signals by increasing the nuclear spin relaxation rate of the protons in water molecules associated with the Gd (III) ion contrast agent, itself having seven unpaired electrons. Another emerging biomedical application of magnetic resonance phenomena is the use of paramagnetic Gd (III) contrast agents as labels for important molecules or cancer cells whose location can be spatially tracked by MR contrast agent response (molecular imaging). Molecular imaging is important to understanding how contrast agent labeled molecules or cells travel though a living animal and the eventual treatment of disease. The molecular imaging process can be made significantly more effective. If multinuclear Gd (III) species can be made by the attachment of several Gd (III) centers to a central molecular collection point and the resulting array bonded to a large cancer-seeking antibody molecule which would target the cancer to be imaged, the efficacy of the MRI process would increase. The aims of this R21 Exploratory/Developmental Grant from the National Cancer Institute are centered on the exploratory synthesis and evaluation of members of a new family of potentially valuable MR contrast agents having the characteristics mentioned above. Structurally, these proposed agents consist of a central collection species comprised of a very stable icosahedral B12(-2) cage. Each vertex, except one, of this B12(-2) cage may be covalently bound to an organic linker arm carrying a DOTA-chelated Gd (III) center. Thus, eleven Gd(lll) contrast agent centers may be attached to a single B12(-2) core which is then connected to a biomolecule capable of selective bonding to a cancer cell to provide molecular imaging. The presence of eleven Gd(lll) MR contrast centers intensifies the observed signal generated per antibody molecule thus enhancing the sensitivity of the method. Studies will be concerned with the chemical synthesis of these new contrast agent structures (closomers), the exploration of new methodologies to increase performance by minimizing intramolecular motion of the Gd(lll) chelate groups, and the development of structures allowing the attachment of biomolecules molecular targeting of cancer.