Development of blood-brain barrier permeable MRI contrast agents

可透过血脑屏障的MRI造影剂的研制

基本信息

批准号：
7803276
负责人：
Maksim Royzen
金额：
$ 5.38万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-09 至 2012-08-08
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7803276
关键词：
Alkaloids Alzheimer&apos s Disease Amyloid Animals Artificial Membranes Biological Biological Assay Blood - brain barrier anatomy Brain Brain Injuries Buffers Carrier Proteins Cattle Cell Membrane Permeability Cerebrum Chromatography Clinical Collaborations Contrast Media Development Disease Endothelial Cells Engineering FDA approved Functional Magnetic Resonance Imaging Gadolinium Goals Health Histocompatibility Testing Image Imaging Device Imaging Techniques Imaging technology In Vitro Injection of therapeutic agent Institutes Laboratories Libraries Life Magnetic Resonance Imaging Malignant Cerebral Neoplasm Massachusetts Membrane Methodology Methods Mission Modeling Molecular Monitor Mus Neuraxis Neurologic Nuclear Omniscan Outcome Pathology Peptides Permeability Phase Phenotype Process Prohance Property Protocols documentation Public Health Quantitative Structure-Activity Relationship Rattus Relaxation Reporting Research Research Design Role Rupture Science Senile Plaques Series Solid Techniques Technology Testing Therapeutic Time Work Zinc aqueous base clinical application design diketopiperazine frontier improved in vitro Assay in vitro testing in vivo novel novel diagnostics outcome forecast public health relevance research study sensor tissue processing tool zinc-binding protein

项目摘要

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.

描述（由申请人提供）：说明申请的广泛、长期目标和具体目标，并参考项目的健康相关性（即与机构使命的相关性）。简明地描述实现这些目标的研究设计和方法。描述您将用于实现这些目标的基本原理和技术。概要本研究的直接目的是设计血脑屏障（BBB）可渗透的磁共振成像（MRI）造影剂。该项目与公共健康直接相关，因为其主要目标是扩大用于大脑 MRI 的钆基造影剂的范围。 MRI 造影剂由于能够区分不同的组织类型，因此在临床应用和研究中具有明显的优势。因此，它们为脑癌、阿尔茨海默病以及与脑损伤相关疾病的成像提供了强大的工具。然而，目前临床上可用的造影剂只能用于研究涉及血脑屏障受损的情况。或者，必须通过颅内注射或破坏血脑屏障进行侵入性给药。 BBB 渗透性 MRI 造影剂将具有更广泛的应用。为了实现血脑屏障渗透性，临床可用的 MRI 造影剂 Omniscan 和 ProScan 将用一系列二酮哌嗪衍生化。后者具有出色的 BBB 渗透性，并且之前已被证明能够充当分子穿梭机，促进高极性化合物跨生物膜的运输。所提出的造影剂将在几种旨在模拟血脑屏障的体外测定中进行测试。它们将包括平行人工膜通透性测定（PAMPA）、固定化人工膜色谱（LAMC）和牛脑微血管内皮细胞（BBMEC）测定。从这些测定中收集的结果将与 BBB 渗透性化合物的特性进行比较，以评估所提出的造影剂对 BBB 渗透性的可能性。根据体外测试的结果，将选择候选人进行活体大鼠的体内实验。将通过对先前施用所建议的造影剂的大鼠的大脑进行 MRI 来测定 BBB 通透性。公共健康相关性：这项研究旨在开发用于大脑磁共振成像的新型工具。这些工具将为脑部疾病的 MRI 开辟新的诊断领域。从广泛的临床角度来看，BBB 渗透性 CA 可以成为规划治疗策略、评估预后和监测治疗进展的宝贵工具。