q-Modulated Magnetic Resonance Imaging Contrast Agents

描述（由申请人提供）：项目摘要/摘要本项目的目标是开发生物活化磁共振（MR）造影剂，用于体内过程的成像，范围从基因表达到第二信使激活。该项目的重点是获得深入了解发育生物学和临床疾病的相互关联的问题，通过i。产生充当实时体内酶报告子的MR探针，ii.跟踪整个动物的基因表达，并将此信息与正在进行的发育事件相关联，以及iii.开发生物相容性支架，用于在实验动物和潜在的人类中有效递送这些药剂。为了最大限度地发挥这种技术的影响，功能性造影剂必须进行研究和开发。此外，对整个动物的发育生物学研究将导致对空间组织与机制的作用的更深入理解。因此，为了创建酶活性的体内测定和第二信使的检测，MR造影剂将被设计和合成为具有可去除的保护基团，其在很大程度上防止水进入顺磁中心。通过限制大量水的进入（q调制），未处理的试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MRI造影剂与酶底物作为封闭基团的水（q-调制）2。使用计算建模来指导新的q调制剂的合成工作。3.开发靶向造影剂和增强造影信号的方法。4.研究药物被细胞内化的传递和摄取机制。5.评价药物在临床前啮齿动物模型和其他体内系统中的有效性。几个四氮杂大环架构将被合成和研究。我们将关注示意性表示的结构I-V，其中箭头表示不可逆活化剂（I-III）的酶攻击位点。

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).