Development of blood-brain barrier permeable MRI contrast agents

说明(由申请人提供)：说明申请的广泛、长期目标和具体目标，并提及项目与健康的相关性(即与机构使命的相关性)。简明扼要地描述实现这些目标的研究设计和方法。描述你将用来实现这些目标的基本原理和技术。本研究旨在设计血脑屏障(BBB)可渗透磁共振成像(MRI)造影剂。该项目与公众健康直接相关，因为它的主要目标是扩大用于脑部核磁共振成像的格拉基造影剂的范围。由于MRI造影剂能够区分不同的组织类型，在临床应用和研究中显示出明显的优势。因此，它们为脑癌、阿尔茨海默病以及与脑损伤相关的疾病提供了强大的成像工具。然而，目前临床上可用的造影剂只能用于研究血脑屏障受损的情况。或者，他们必须侵入性地给药，通过颅内注射或通过打破血脑屏障。BBB透气性磁共振造影剂将有更广阔的应用前景。为了实现血脑屏障的渗透性，临床上可用的核磁共振造影剂Omniscan和ProScan将被一系列的二酮吡喃类药物衍生化。后者具有良好的血脑屏障渗透性，以前被证明能够充当分子穿梭，促进高极性化合物在生物膜上的运输。建议的造影剂将在几种旨在模拟血脑屏障的体外试验中进行测试。它们将包括平行人工膜通透性分析(PAMPA)、固定化人工膜色谱(LAMC)和牛脑微血管内皮细胞(BBMEC)分析。从这些检测中收集的结果将与血脑屏障透过性化合物的性质进行比较，以评估建议的造影剂对血脑屏障通透性的可能性。根据体外测试的结果，将选择候选人进行活体实验。血脑屏障通透性将通过对先前使用建议造影剂的大鼠的大脑进行磁共振成像来进行分析。 与公共健康相关：这项研究旨在开发脑部磁共振成像的新工具。这些工具将为脑部疾病的磁共振成像开辟新的诊断前沿。从广泛的临床角度来看，血脑屏障通透性CA可以成为制定治疗策略、评估预后和监测治疗进展的有价值的工具。

DESCRIPTION (provided by applicant): State the application's broad, long-term objectives and specific aims, making reference to the health relatedness of the project (I.e., relevance to the mission of the agency). Describe concisely the research design and methods for achieving these goals. Describe the rationale and techniques you will use to pursue these goals. SUMMARY This research is immediately aimed at designing blood-brain barrier (BBB) permeable magnetic resonance imaging (MRI) contrast agents. The project is directly related to public health since its main objective is to broaden the scope of gadolinium-based contrast agents for the MRI of the brain. MRI contrast agents present distinct advantages in clinical applications and research due to their ability to differentiate between different tissue types. Thus, they offer powerful tools for imaging of cerebral cancers, Alzheimer's disease, as well as conditions associated with brain damage. However, the contrast agents clinically available today can only be used to study conditions involving compromised BBB. Alternatively, they have to be administered invasively, by intracranial injection or by rupturing the BBB. BBB permeable MRI contrast agents will have much broader applications. To achieve BBB permeability, clinically available MRI contrast agents, Omniscan and ProScan will be derivatized with a series of diketopiperizines. The latter have excellent BBB permeability and were previously shown to be capable of acting as molecular shuttles, facilitating transport of highly polar compounds across biological membranes. The proposed contrast agents will be tested in several in vitro assays designed to mimic BBB. They will include parallel artificial membrane permeability assay (PAMPA), immobilized artificial membrane chromatography (lAMC), and bovine brain microvessel endothelial cell (BBMEC) assay. The results gathered from these assays will be compared to the properties of BBB permeable compounds to assess the likelihood of BBB permeability by the proposed contrast agents. Based on the outcome from in vitro testing, candidates will be selected for in vivo experimentation using live rats. BBB permeability will be assayed by performing MRI of the brain of rats previously administered with the proposed contrast agents. PUBLIC HEALTH RELEVANCE: This research is aimed at developing novel tools for magnetic resonance imaging of the brain. These tools will open up new diagnostic frontiers for the MRI of cerebral disorders. From a broad clinical perspective BBB permeable CAs could become valuable tools in planning therapeutic strategy, assessing prognosis and monitoring treatment progress.