Novel PET imaging agents for early diagnosis of plaque deposition in Alzheimer's

用于早期诊断阿尔茨海默病斑块沉积的新型 PET 显像剂

• 批准号: 7842412
• 负责人: Padmakar Kulkarni
• 金额: $ 37.68万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7842412
• 关键词: Address; Affect; Affinity; Age; Aging; Alzheimer' s Disease; American; Amyloid; Amyloid Proteins; Amyloid beta-Protein; Animal Model; Animals; Antioxidants; Area; Autopsy; Benzene; Binding; Biodistribution; Biological Assay; Biological Markers; Biological Markers; Blood; Brain; Brain Pathology; Buffers; Carbon; Cessation of life; Characteristics; Chelating Agents; Cholesterol; Clinical; Clinical Trials; Clioquinol; Cyclotrons; Data; Degenerative Disorder; Dementia; Deposition; Detection; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Drug Kinetics; Dyes; Early Diagnosis; Early treatment; Elderly; Fluorine; Free Radicals; Future; Generations; Goals; Heart Diseases; Histopathology; Human; Hydrogen Peroxide; Hydrophobicity; Image; In Vitro; Individual; Inhibitory Concentration 50; Ions; Label; Laboratories; Lead; Life; Life Expectancy; Ligands; Long-Term Care; Measures; Memory Loss; Mental disorders; Metals; Methods; Molecular; Mus; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Neuropsychological Tests; Octanols; Oxyquinoline; PET/CT scan; Partition Coefficient; Pathogenesis; Patient Care; Patients; Peptides; Permeability; Polyethylene Glycols; Population; Positron-Emission Tomography; Process; Property; Proteins; Radio; Radioactive; Radioisotopes; Reporting; Research; Research Personnel; Running; Scanning; Senile Plaques; Serum; Side; Slide; Staging; Staining method; Stains; Stress; Structure; Technology; Testing; Therapeutic Uses; Time; Tissues; Toxic effect; Tracer; Transgenic Animals; Transgenic Organisms; Transition Elements; Translating; Treatment Cost; Validation; Work; analog; base; beta-site APP cleaving enzyme 1; brain cell; brain tissue; clinical Diagnosis; cost; disease diagnosis; economic implication; extracellular; imaging modality; imaging probe; in vivo; inhibitor/antagonist; interest; lipophilicity; metal chelator; metal complex; mind control; molecular imaging; neuroimaging; neuron loss; neuropathology; novel; novel therapeutic intervention; older patient; peptide A; preempt; prevent; productivity loss; protein aggregate; public health relevance; pyridine; quinoline; quinoline analog; radiotracer; research study; response; social; tau Proteins; therapeutic development; tool; uptake; vaccine development

DESCRIPTION (provided by applicant):This application addresses Challenge Area (03) Biomarker Discovery and Validation. (RFA-OD-09-003) 03- MH-101, Biomarkers in mental disorders. The goal of the proposal is to develop biomarkers for the detection of amyloid plaques in living humans. Successful development of these biomarkers would allow for detection of amyloid burden in subjects with Alzheimer's disease (AD) and also would allow for specific and accurate early diagnosis and disease progression and disease modifying treatments. This is significant at a time when a number of therapies for AD are in clinical trial including the use of antioxidants, BACE and gamma secratase inhibitors and metal chelators. Elevated levels of metals (Cu, Zn and Fe) in amyloid plaque are targets for development of therapeutic and diagnostic agents. Metal chelators are showing promise for the treatment of AD. We plan to develop F-18 labeled analogs of 8-hydroxyquinoline (HQ), a weak metal (Zn, Cu) chelator, as PET imaging agents for early diagnosis of AD. These agents would be unique in targeting metal-protein aggregates in amyloid plaques. Toxicity issues associated with clioquinol are not likely to be problems with diagnostic agents' 8- hydroxyquinoline based derivative, since the amount of these compounds administered for diagnostic purpose are sub-pharmacological levels, several orders of magnitude lower than the amounts used for therapeutic purpose. Alzheimer's disease (AD) is a debilitating neurodegenerative disorder that largely affects the elderly. The most significant pathological characteristic in the post-mortem AD brain is the presence of extracellular plaque deposits and intracellular neurofibrillar tangles. Believed to be pathogenesis of AD, the process of plaque deposition commences decades before the clinical diagnosis is possible. Plaque is comprised of aggregated fibrils of beta amyloid (A¿) collocated with transition metal ions such as Zn, Cu, and Fe, that are present in the brain. These metal-protein aggregates are thought to be toxic, involved in generation of H2O2 and free radicals causing neuronal damage. Recent studies indicated that at an early stage of the disease it may be possible to disaggregate the plaque, reverse neuronal loss, and treat AD. Early diagnosis of AD pathogenesis at a molecular level would allow for these other interventional approaches to preempting AD. The goal of the project is to develop novel [18F] labeled imaging agents targeting amyloid protein-metal complex aggregates in Alzheimer's disease. Ante-mortem diagnosis of Alzheimer's based on neuropsychological tests are inconclusive at early stages of the disease and clinical PET imaging with [18F]FDG is suboptimal for differentiating various dementias. Ongoing efforts have led to the development f PET imaging agents, as [11C]PIB, [18F]FDDNP, [124]IMP, [18F]AV-45, [11C]SB-13, all of which are promising for labeling A¿ amyloid protein. They bind to varying hydrophobic binding pockets within A¿ proteins. However, all agents displayed significant weaknesses in in vivo imaging studies. They bind to varying hydrophobic binding pockets within A¿ proteins. However, all agents displayed significant weaknesses in in vivo imaging studies either with respect to high non-specific uptake, slow clearance from non-amyloid centers, or an inability to distinguish the various forms of plaque, which compromised their ability to unequivocally distinguish and quantify plaque. We plan to synthesize a number of fluorinated analogs of 8-hydroxy quinoline, characterize them and test them for their affinity for Zn-Abeta peptide aggregates. Selective compounds with high amyloid binding affinity will be labeled with F-18. We will test for their lipophilicity and perform ex vivo and in vivo studies. We have successfully prepared [18F]2F-HQ and initial micro PET/CT imaging studies in mice with this compound have shown desirable properties; high initial brain uptake (5-8 %ID/g) and rapid washout from normal mouse brain. These preliminary results are quite encouraging and warrant further development of this class of molecules as potential AD imaging agents. A successful [18F]HQ analog with desirable in vivo properties with high amyloid binding affinity, will be highly useful invention for the early diagnosis of AD pathogenesis. An accurate, noninvasive, molecular imaging method to assist in the early diagnosis of Alzheimer's plaque would be highly useful not only for early detection but also for following disease progression and as a biomarker for assessing new disease-modifying treatments for AD. PUBLIC HEALTH RELEVANCE: It would be desirable to develop a test that will identify the biological markers of Alzheimer's disease, much like cholesterol now serving as a biomarker of heart disease. Researchers are working on the development of vaccines and other treatment options. Such developments would be a huge breakthrough for a disease that has no cure and can only be diagnosed after death when a patients' brain is autopsied. Experts in the field stress the importance of diagnosing the disease at an early stage, since patients would do better if they are identified earlier. Alzheimer's is the most common form of dementia afflicting more than 5 million Americans. As the population ages, the Alzheimer's Association expects half a million new cases a year, with 10 million baby boomers eventually the degenerative disease that is fatal. According to some estimates collateral loss of productivity and associated annual costs for diagnosis, treatment, and short-and long term care totaling nearly 100 billion dollars annually to the US economy. In the next 20 years, this figure is projected to double and the costs rise to $380 billion annually. With increasing life expectancy and aging baby-boomer generation, the estimated future costs of treatment and elderly patient care, and its socio-economic implications are staggering. Two pronged early detection and early treatment is the required approach in averting this looming social and financial crisis. Amyloid is the dangerous brain plaque and tau protein tangles with in the brain cells tend to prevent neurons from communicating each other leading to loss of memory. Positron emission tomography (PET scan) can create image of the harmful beta amyoid plaque in the brains of living Alzheimer's patients. Currently used dye has very short life time (requiring an onsite cyclotron machine to produce it) limits its accessibility. It would be desirable to develop a longer lasting new radioactive agent that can be injected into patients to be scanned. We plan to develop such an agent. We plan to synthesize a number of molecules and screen them for their ability to bind to the amyloid plaque. Promising candidate molecules will be tagged with a radioisotope [18F] will be tested in using laboratory assays and imaging the animals with Alzheimer's disease with a (micro) PET scanner. A successful agent will be highly useful invention not only for early detection of but also for following disease progression and as biomarker for assessing disease-modifying treatments for Alzheimer's disease.

描述（由申请人提供）：本申请涉及挑战领域（03）生物标志物的发现和验证。（RFA-OD-09-003） 03- MH-101，精神障碍的生物标志物。该提案的目标是开发用于检测活体淀粉样斑块的生物标志物。这些生物标志物的成功开发将允许检测阿尔茨海默病（AD）受试者的淀粉样蛋白负担，也将允许特定和准确的早期诊断和疾病进展以及疾病修饰治疗。目前，许多治疗阿尔茨海默病的方法都处于临床试验阶段，包括使用抗氧化剂、BACE、γ - secratase抑制剂和金属螯合剂。淀粉样斑块中金属（Cu， Zn和Fe）水平的升高是开发治疗和诊断药物的目标。金属螯合剂在治疗阿尔茨海默病方面显示出前景。我们计划开发F-18标记的8-羟基喹啉（HQ）类似物，一种弱金属（Zn, Cu）螯合剂，作为早期诊断AD的PET显像剂。这些药物在靶向淀粉样斑块中的金属蛋白聚集体方面是独一无二的。与氯喹诺相关的毒性问题不太可能是诊断试剂的8-羟基喹啉衍生物的问题，因为用于诊断目的的这些化合物的剂量是亚药理学水平，比用于治疗目的的剂量低几个数量级。阿尔茨海默病（AD）是一种使人衰弱的神经退行性疾病，主要影响老年人。死后AD脑最显著的病理特征是细胞外斑块沉积和细胞内神经纤维缠结的存在。斑块沉积被认为是阿尔茨海默病的发病机制，在临床诊断可能之前几十年就开始了。斑块是由β淀粉样蛋白（A¿）聚集的原纤维与存在于大脑中的过渡金属离子（如锌、铜和铁）结合而成。这些金属-蛋白质聚集体被认为是有毒的，参与H2O2和自由基的产生，导致神经元损伤。最近的研究表明，在疾病的早期阶段，有可能分解斑块，逆转神经元损失，并治疗阿尔茨海默病。在分子水平上对阿尔茨海默病发病机制的早期诊断将允许这些其他介入方法来预防阿尔茨海默病。该项目的目标是开发针对阿尔茨海默病淀粉样蛋白-金属复合物聚集体的新型[18F]标记显像剂。在疾病的早期阶段，基于神经心理学测试的阿尔茨海默病的死前诊断是不确定的，使用[18F]FDG进行临床PET成像对于区分各种痴呆症是不理想的。不断的努力导致PET显像剂的发展，如[11C]PIB， [18F]FDDNP, [124]IMP, [18F]AV-45, [11C]SB-13，所有这些都有希望标记A¿淀粉样蛋白。它们与A¿蛋白中不同的疏水结合口袋结合。然而，所有药物在体内成像研究中都显示出明显的弱点。它们与A¿蛋白中不同的疏水结合口袋结合。然而，所有药物在体内成像研究中都表现出明显的弱点，要么是非特异性摄取高，从非淀粉样蛋白中心清除缓慢，要么无法区分各种形式的斑块，这损害了它们明确区分和量化斑块的能力。我们计划合成一些8-羟基喹啉的氟化类似物，对它们进行表征并测试它们对锌- β肽聚集体的亲和力。具有高淀粉样蛋白结合亲和力的选择性化合物将用F-18标记。我们将测试它们的亲脂性，并进行离体和体内研究。我们已经成功制备了[18F]2F-HQ，该化合物在小鼠体内的初步微PET/CT成像研究显示出了理想的特性；高初始脑摄取（5- 8% ID/g）和从正常小鼠脑中快速冲洗。这些初步结果非常令人鼓舞，并保证了这类分子作为潜在的AD显像剂的进一步发展。一种成功的[18F]HQ类似物具有理想的体内特性和高淀粉样蛋白结合亲和力，将是对AD发病机制的早期诊断非常有用的发明。一种准确的、无创的分子成像方法有助于阿尔茨海默氏斑块的早期诊断，不仅对早期发现非常有用，而且对疾病进展的跟踪也非常有用，可以作为评估阿尔茨海默氏症新的疾病改善治疗方法的生物标志物。