q-Modulated Magnetic Resonance Contrast Agents

q-调制磁共振造影剂

• 批准号: 6907040
• 负责人: Thomas J Meade
• 金额: $ 24.58万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-23 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6907040
• 关键词: bioimaging /biomedical imaging; chemical synthesis; contrast media; enzyme activity; enzyme substrate; hydropathy; image enhancement; laboratory mouse; magnetic resonance imaging; molecular /cellular imaging; molecular probes; pharmacokinetics; second messengers

DESCRIPTION (provided by applicant): The long-range goal of this project is to develop bioactivated magnetic resonance (MR) contrast agents for imaging in vivo process from gene expression to secondary messenger activation. This project is focused on obtaining insights into the interrelated problems of developmental biology and clinical diseases by i. generating MR probes that function as real-time in vivo enzyme reporters, ii. tracking gene expression in whole animals and correlate this information with on going developmental events, and iii. developing biocompatible scaffolds for the efficient delivery of agents in experimental animals, and ultimately humans. It is clear that MR imaging has become one of the most important tools for the diagnosis of a range of clinical problems and in order to maximize the impact of this technique, functional contrast agents must be investigated and developed. Further, the study of developmental biology in whole-animals using a modality that provides temporal resolution, coupled with bioactivated MR contrast agents will result in a deeper understanding of the role of spatial organization with mechanism. Therefore, to create an in vivo MRI assay of enzymatic activities and secondary messengers, MR contrast agents will be designed and synthesized with removable protection groups that largely prevent access of water to a paramagnetic center. By limiting the access of bulk water (q-modulation) the unprocessed agent is designed to be an ineffective contrast agent. Five macrocyclic platforms will be used to generate reversible and irreversible MR reporters of enzymes and secondary messengers that include: sugars, peptides, calcium, phosphorylation. Complexes will be designed, tested and optimized for Beta-galactosidase, Beta-glucoronidase, caspases, MMP's, cathepsin, kinases, and intracellular calcium. We have defined five primary objectives: I. Synthesize and characterize MRI contrast agents with enzyme substrates as water blocking groups of (q-modulation). II. Investigate the relationship between the structure of the agent with observed contrast enhancement, enzyme kinetics, clearance and toxicity. III. Develop intracellular delivery vehicles for MR contrast agents. IV. Synthesize multimodal probes for in vivo validation and co-registration. V. Evaluate the effectiveness of the bioactivated contrast agents in vitro and in vivo.

描述(申请人提供)：该项目的长期目标是开发生物激活磁共振(MR)造影剂，用于体内从基因表达到二次信使激活的过程。这个项目的重点是通过I产生作为实时体内酶报告的MR探针来获得对发育生物学和临床疾病相互关联的问题的洞察，II。跟踪整个动物的基因表达，并将这一信息与正在进行的发育事件相关联，以及开发生物相容的支架，用于在实验动物和最终人类中有效地传递药物。 显然，磁共振成像已经成为诊断一系列临床问题的最重要的工具之一，为了最大限度地发挥这项技术的影响，必须研究和开发功能性造影剂。此外，使用一种提供时间分辨率的模式来研究整个动物的发育生物学，再加上生物激活的磁共振造影剂，将导致对具有机制的空间组织的作用的更深层次的理解。因此，为了建立酶活性和二级信使的体内MRI分析，将设计和合成具有可拆卸保护基团的MR造影剂，这些保护基团在很大程度上阻止水进入顺磁中心。通过限制散装水的进入(调Q)，未经处理的造影剂被设计为无效的造影剂。五个大环平台将被用来产生可逆和不可逆的酶和二级信使的MR记者，包括：糖、肽、钙、磷酸化。将设计、测试和优化β-半乳糖苷酶、β-葡萄糖苷酶、半胱氨酸氨基转移酶、基质金属蛋白酶、组织蛋白酶、激动酶和细胞内钙的复合体。我们定义了五个主要目标： 1.以酶为底物的水封闭基团(调Q)MRI造影剂的合成与表征。 研究造影剂的结构与观察到的对比剂增强、酶动力学、清除度和毒性的关系。 开发磁共振造影剂的细胞内给药载体。 IV.合成用于体内验证和联合注册的多模式探针。 评价生物活性造影剂的体内外效果。