Novel MRI Contrast Agent for Detection of Beta Amyloid

用于检测 β 淀粉样蛋白的新型 MRI 造影剂

• 批准号: 9253759
• 负责人: Peter Working
• 金额: $ 94.26万
• 依托单位: ALZECA BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-15 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9253759
• 关键词: Affect; Affinity; Age; Age-Months; Alpha Particles; Alzheimer' s Disease; American; Amyloid; Amyloid beta-Protein; Animals; Binding; Biological Markers; Biological Sciences; Blood - brain barrier anatomy; Blood Vessels; Brain; Canis familiaris; Cause of Death; Cerebral cortex; Clinical Trials; Complex; Contracts; Contrast Media; Coupled; Data; Dementia; Deposition; Detection; Diagnostic; Diagnostic Imaging; Disease; Dose; Drug Kinetics; FDA approved; Foundations; Funding; Future; Genotype; Goals; Grant; Hippocampus (Brain); Human; Image; Imagery; Imaging technology; In Vitro; Individual; Injectable; Injection of therapeutic agent; Intravenous; Journals; Label; Ligands; Liposomes; Magnetic Resonance; Magnetic Resonance Imaging; Manufacturer Name; Medical center; Modeling; Molecular Target; Monkeys; Mus; Names; Noise; Paper; Pathology; Patients; Pharmaceutical Preparations; Phase; Positron-Emission Tomography; Preparation; Process; Production; Property; Radiochemistry; Radioisotopes; Relaxation; Resolution; Risk; Rodent; Safety; Senile Plaques; Signal Transduction; Site; Small Business Innovation Research Grant; Specialized Center; Structure of choroid plexus; Tetracycline Control; Tg2576; Toxic effect; Toxicology; United States; aged; amyloid imaging; analog; base; brain tissue; cost; imaging agent; imaging system; improved; in vivo; interest; intravenous injection; iron oxide; meetings; molecular imaging; mouse model; mutant; nanoparticle; nonhuman primate; novel; overexpression; particle; presenilin-1; tool

Project Summary Alzheimer's disease (AD) is the most common form of dementia, affecting roughly 5.5 million Americans, and is the sixth leading cause of death in the United States. Quantification of amyloid (Aβ) plaque burden with 18F and 11C- based Positron Emission Tomography (PET) imaging agents, based on high affinity Aβ aggregate-binding radionuclides shows promise for identifying individuals with increased risk of progressing to AD. However, PET imaging has several drawbacks including high cost, limited access, and poor spatial resolution. Furthermore, PET involves radiochemistry, which is both expensive and complex, thereby limiting distribution potential to specialized medical centers with radiochemistry capabilities. This Phase II project will seek to further develop “ADx-Magnetic Resonance(MR)”, a targeted liposomal contrast agent that will be used in conjunction with 1.5T MR imaging systems, which are far more readily available than PET imaging systems, and much less expensive to use. The primary objectives of this Phase II grant is to gather safety/pharmacokinetic data in both small and large animals, and to transfer the synthesis process to a contract manufacturer in preparation for future GLP studies. ADx-MR has the potential to provide imaging of AD pathology at high resolution, and a significantly lower cost, with 5-10x more patient access points, than PET amyloid imaging. Coupled with the exceptional spatial resolution of MR Imaging, this agent enables the visualization of features at a voxel size of 100 µm, a significant improvement over PET approaches with centimeter size voxels. To date, this novel, intravenously delivered Aβ-targeted liposome, ADx, has proven successful in in-vivo studies in three Alzheimer's mouse models. Alzeca has also performed dose ranging studies in mice and pilot PK studies in non-human primates. The goal of this project is therefore to advance ADx-MR, a liposomal T1-MR agent to qualify for a pre-IND meeting by establishing additional efficacy, safety, and scalability data.

项目摘要 阿尔茨海默氏病（AD）是痴呆症的最常见形式， 大约有550万美国人，是美国第六大死亡原因。 美国的用18F和11 C-β-淀粉样蛋白（Aβ）斑块负荷定量 基于正电子发射断层扫描（PET）成像剂，基于高 亲和力Aβ聚集体结合放射性核素显示出识别 进展为AD的风险增加的个体。然而，PET成像具有 一些缺点，包括高成本、有限的访问和差的空间 分辨率此外，PET涉及放射化学，其既昂贵 和复杂，从而限制了分配潜力，以专门的医疗中心 放射化学能力。 该第二阶段项目将寻求进一步开发“ADx-磁性 共振（MR）"，一种靶向脂质体造影剂，将用于 与1.5T MR成像系统结合使用， 比PET成像系统更便宜。主 这项II期资助的目的是收集两种药物的安全性/药代动力学数据， 小型和大型动物，并将合成过程转移到合同中 为将来的GLP研究做准备。 ADx-MR有可能在高水平下提供AD病理学成像， 分辨率，成本显著降低，患者接入点增加5- 10倍， 比PET淀粉样蛋白成像更好。再加上卓越的空间分辨率， MR成像，该试剂能够以 100 µm，与采用厘米尺寸的PET方法相比有显著改进 体素 迄今为止，这种新型的静脉内递送的Aβ靶向脂质体，ADx， 已经在三种阿尔茨海默氏症小鼠模型的体内研究中证明是成功的。 Alzeca还在小鼠中进行了剂量范围研究，并在 非人类灵长类动物因此，该项目的目标是推进ADx-MR， 脂质体T1-MR药物，通过建立额外的 有效性、安全性和可扩展性数据。