q-Modulated Magnetic Resonance Imaging Contrast Agents

描述(申请人提供)：项目摘要/摘要本项目的目标是开发生物激活磁共振(MR)造影剂，用于体内过程的成像，范围从基因表达到二次信使激活。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，并将这些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，以便在实验动物和潜在的人类中有效地传递这些药物。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，对整个动物的发育生物学的研究将导致对具有机制的空间组织的作用的更深入的理解。因此，为了建立酶活性的体内分析和二级信使的检测，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。我们定义了5个主要目标：1.合成和表征以酶为底物的水封闭基团磁共振造影剂(调Q)2.利用计算模型指导合成新的调Q试剂。3.开发有针对性的造影剂和放大对比信号的方法。4.研究药物在细胞内的转运和摄取机制。5.评价药物在临床前啮齿动物模型和其他活体系统中的有效性。我们将合成并研究几种四氮杂大环化合物。我们将集中在示意性表示的结构I-V上，其中箭头表示不可逆激活剂(I-III)的酶攻击位置。 公共卫生相关性：该项目与公共卫生相关，因为其结果将直接影响目前临床疾病的诊断和治疗方法。生物活性造影剂的发展是发育生物学的有力工具，在肿瘤转移预防等领域有着广泛的应用。

DESCRIPTION (provided by applicant): Project Summary/Abstract The goal of this project is to develop bioactivated magnetic resonance(MR) contrast agents for the imaging of in vivo processes, ranging 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. Track gene expression in whole animals and correlate this information with ongoing developmental events, and iii. develop biocompatible scaffolds for the efficient delivery of these agents in experimental animals and potentially humans. 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 will result in a deeper understanding of the role of spatial organization with mechanism. Therefore, to create an in vivo assay of enzymatic activities and detection of secondary messengers, MR contrast agents will be designed and synthesized with removable protection groups that largely prevent the 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. We have defined 5 primary objectives: 1.Synthesize and characterize MRI contrast agents with enzyme substrates as blocking groups of water (q-modulation) 2. Use computational modeling to direct synthetic efforts towards new q-modulated agents. 3.Develop targeted contrast agents and methods of amplifying the contrast signal. 4. Investigate delivery and the uptake mechanisms by which the agents are internalized by cells. 5. Evaluate the effectiveness of the agents in preclinical rodent models and other in vivo systems. Several tetraazamacrocyclic architectures will be synthesized and investigated. We will focus on the schematically represented structures I- V where the arrows represent the site of enzymatic attack for the irreversibly activated agents (I-III). PUBLIC HEALTH RELEVANCE: This project is relevant to public health because the results will directly impact current methods of diagnosis and treatment of clinical disease. The development of bioactivated contrast agents for tracking gene expression is a powerful tool for developmental biology which has wide-ranging applications in areas such as prevention of cancer metastasis.