Development of blood-brain barrier permeable MRI contrast agents

可透过血脑屏障的MRI造影剂的研制

• 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
• 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' 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

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.

说明（由申请人提供）：说明申请的广泛、长期目标和具体目的，并提及项目与健康的相关性（即，与原子能机构的使命相关）。简要描述研究设计和实现这些目标的方法。描述你将用来实现这些目标的原理和技术。本研究旨在设计可透过血脑屏障（BBB）的磁共振成像（MRI）造影剂。该项目与公共卫生直接相关，因为其主要目标是扩大用于脑部MRI的钆基造影剂的范围。MRI造影剂由于其区分不同组织类型的能力而在临床应用和研究中呈现出明显的优势。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受损BBB的情况。或者，它们必须通过颅内注射或通过破坏BBB侵入性地施用。血脑屏障渗透性MRI造影剂将有更广泛的应用。 为了实现BBB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。后者具有优异的BBB渗透性，并且先前显示能够充当分子穿梭机，促进高极性化合物穿过生物膜的运输。将在几项旨在模拟BBB的体外试验中对拟定造影剂进行检测。它们包括平行人工膜渗透性测定（PAMPA）、固定化人工膜色谱（IAMC）和牛脑微血管内皮细胞（BBMEC）测定。将从这些试验中收集的结果与BBB渗透性化合物的性质进行比较，以评估申报造影剂对BBB渗透性的可能性。根据体外试验的结果，将选择候选物用于使用活大鼠的体内实验。将通过对先前给予拟定造影剂的大鼠的大脑进行MRI来测定BBB渗透性。 公共卫生相关性：这项研究旨在开发大脑磁共振成像的新工具。这些工具将为脑部疾病的MRI诊断开辟新的前沿。从广泛的临床角度来看，血脑屏障渗透性CAs可能成为制定治疗策略、评估预后和监测治疗进展的有价值的工具。