q-Modulated Magnetic Resonance Imaging Contrast Agents

项目概述/摘要该项目的目标是开发生物活性磁共振（MR）造影剂，用于体内过程的成像，从基因表达到次级信使激活。该项目的重点是通过以下方法获得对发育生物学和临床疾病相关问题的见解：1 .生成具有实时体内酶报告功能的MR探针；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联系起来；开发生物相容性支架，以便在实验动物和潜在的人类中有效地递送这些药物。为了使这项技术的影响最大化，必须研究和开发功能性造影剂。此外，对全动物发育生物学的研究将有助于我们对空间组织的作用和机制有更深入的认识。因此，为了创建体内酶活性检测和二级信使检测，将设计和合成具有可移动保护基团的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。通过限制大量水的进入（q-调制），未处理的造影剂被设计成无效的造影剂。我们确定了5个主要目标：1。用酶底物作为水的阻断基团合成和表征MRI造影剂（q-调制）使用计算模型来指导合成新的q-调制剂。3.开发有针对性的造影剂和增强造影剂信号的方法。4. 研究药物被细胞内化的传递和摄取机制。5. 评估药物在临床前啮齿类动物模型和其他体内系统中的有效性。将合成和研究几种四氮杂环结构。我们将重点关注图解表示的结构I- V，其中箭头表示不可逆活性剂（I- iii）的酶攻位点。

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). 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.