q-Modulated Magnetic Resonance Contrast Agents

描述（由申请人提供）：本项目的长期目标是开发生物活化磁共振（MR）造影剂，用于从基因表达到次级信使激活的体内过程成像。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.跟踪整个动物中的基因表达并将该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，用于在实验动物和最终人类中有效递送药剂。 很明显，磁共振成像已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，功能性造影剂必须进行研究和开发。此外，在整个动物的发育生物学的研究，使用的方式，提供时间分辨率，加上生物激活的MR造影剂将导致空间组织的作用与机制的更深入的理解。因此，为了创建酶活性和第二信使的体内MRI测定，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），未处理的造影剂被设计为无效的造影剂。五个大环平台将用于产生酶和第二信使的可逆和不可逆MR报告分子，包括：糖，肽，钙，磷酸化。将针对β-半乳糖苷酶、β-葡萄糖醛酸酶、半胱天冬酶、MMP、组织蛋白酶、激酶和细胞内钙设计、测试和优化复合物。我们确定了五个主要目标： I.合成和表征MRI造影剂与酶底物作为水阻断基团（调Q）。 二.研究造影剂结构与观察到的造影增强、酶动力学、清除率和毒性之间的关系。 三.开发MR造影剂的细胞内递送载体。 四.合成用于体内验证和共配准的多模式探针。 诉评价生物活性造影剂的体外和体内有效性。

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.