Novel MRI Probes for In Vivo Molecular Imaging

描述（由申请人提供）： 使用磁共振成像（MRI）在体内对分子靶标进行非侵入性成像的能力代表了诊断成像领域的重大进步。在这个项目中，我们建议开发新的MRI探针，这将允许成像的基质金属蛋白酶（MMPs）在体内的表达。MMPs在许多病理过程中过度表达，包括癌症、心血管疾病、炎症和免疫性疾病。在中枢神经系统中，已知MMPs在高级别胶质瘤和多发性硬化症（MS）中过度表达。成像MMPs在体内水平的能力将对我们理解这些疾病过程、它们对治疗的反应以及我们开发新的、更有效的药理学试剂的能力产生深远的影响。 在本项目的第一阶段（R21），我们将开发新型MRI探针，并在大鼠CS胶质瘤模型上进行评估。这一阶段有三个具体目标： 具体目标#1：开发MMP-2活化的渗透性调节剂。 具体目标#2：开发MMP-2活化的有机金属基探针。 具体目标#3：CS胶质瘤模型中MMP-2表达的体内成像。 在该项目的第二阶段（R33）中，我们将扩展这项新技术以研究其他病理过程，并评估我们的血管渗透性探针改善药物局部递送的能力。这一阶段有三个具体目标： 具体目标#1：人肿瘤异种移植物中MMP-2表达的体内成像。 具体目标#2：MS大鼠EAE模型中MMP-9表达的体内成像。 具体目标#3：评价血管通透性调节剂改善药理学试剂治疗效果的能力。

DESCRIPTION (provided by applicant): The ability to non-invasively image molecular targets in vivo using magnetic resonance imaging (MRI) represents a major advance in the field of diagnostic imaging. In this project, we propose to develop novel MRI probes which will allow for imaging of the expression of matrix metalloproteinases (MMPs) in vivo. MMPs are over expressed in many pathological process, including cancer, cardiovascular, inflammatory, and immune diseases. In the central nervous system, MMPs are known to be over expressed in high-grade gliomas and multiple sclerosis (MS). The ability to image the levels of MMPs in vivo will have profound ramifications on cur understanding of these disease process, their response to treatment, and our ability to develop new, more effective pharmacological agents. In Phase I (R21) of this project, we will develop the novel MRI probes and evaluate them on a rat CS glioma model. This phase has three specific aims: Specific Aim #1: Development of a MMP-2 activated permeability modulator. Specific Aim #2: Development of a MMP-2 activated organometallic-based probe. Specific Aim #3: In vivo imaging of MMP-2 expression in a CS glioma model. In Phase II (R33) of this project, we will extend this new technology to study other pathological processes, as well as evaluate the ability of our vascular permeability probe to improve local delivery of pharmacological agents. This phase has three specific aims: Specific Aim #1: In vivo imaging of MMP-2 expression in human tumor xenografts. Specific Aim #2: In vivo imaging of MMP-9 expression in a rat EAE model of MS. Specific Aim #3: Evaluation of the ability of vascular permeability modulator to improve the therapeutic efficacy of pharmacological agents.