Technetium-99M Labeled SPECT Agents for Imaging B-amyloid in Alzheimer's Disease

Technetium-99M 标记的 SPECT 试剂用于对阿尔茨海默病中的 B 淀粉样蛋白进行成像

• 批准号: 7295890
• 负责人: Vijay Sharma
• 金额: $ 19.38万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7295890
• 关键词: Age; Alzheimer' s Disease; American; Amyloid; Amyloid Proteins; Amyloid beta-Protein Precursor; Animal Model; Appearance; Astrocytes; Binding; Biochemical; Biodistribution; Biological Assay; Brain; Brain region; Capillary Endothelial Cell; Cell surface; Cells; Characteristics; Chelating Agents; Choline; Clinical; Clinical Trials; Clioquinol; Control Animal; Copper; Deposition; Detection; Development; Diagnosis; Diagnostic; Disease Management; Disorientation; Drug Kinetics; Early Diagnosis; Evaluation; Event; Freezing; Galantamine; Generations; Health Care Costs; Hippocampus (Brain); Human; Ibuprofen; Image; Impaired cognition; Impairment; Injection of therapeutic agent; Investigation; Isotopes; Language; Lead; Learning; Medical Imaging; Memantine; Memory; Memory Loss; Methods; Microglia; Molecular Target; Monitor; Mus; Neurites; Neurodegenerative Disorders; Neurofibrillary Tangles; Patients; Penetration; Peptides; Pharmaceutical Preparations; Property; Protein Family; Proteins; Radiopharmaceuticals; Senile Plaques; Specificity; Staging; Staining method; Stains; Structure-Activity Relationship; Symptoms; System; Tail; Technetium 99m; Testing; Therapeutic; Transgenic Mice; United States Food and Drug Administration; Variant; Veins; Zinc; analog; base; chelation; cost efficient; design; esterase inhibitor; extracellular; human tissue; in vivo; inhibitor/antagonist; mouse model; neuron loss; novel; protein aminoacid sequence; radiotracer; rivastigmine; secretase; single photon emission computed tomography; uptake

DESCRIPTION (provided by applicant): A noninvasive method for detection and quantification of ¿-amyloid plaques (A¿) in vivo would have wide utility for premortem diagnosis of Alzheimer's Disease (AD) and monitoring anti-amyloid therapy. While several PET-based agents are under development, an easily accessible, efficient, and highly specific technetium-99m-based SPECT imaging agent would be highly desirable. While exploring peptide-based agents for biomedical applications, we have discovered a small peptide that accommodates technetium-99m, the most commonly used isotope in medical imaging. Our lead 99mTc-peptide binds specifically to A¿ in a concentration-dependent and saturable manner. The agent remains nonmetabolized and a fluorescent analogue of the lead agent shows staining of A¿ plaques in brain sections of APPsw+/- transgenic mice compared with none in their age-matched WT controls. Importantly, 2 hr following tail-vein injection of the 99mTc-peptide, phosphorimaging of frozen brain sections of APPsw+/- transgenic mice and age-matched controls demonstrates a selective retention of radiotracer in APPsw+/- mice and only background binding in controls. We now propose to evaluate the impact of various chelating cores on the targeting properties of our lead agent to define structure-activity relationships in guiding the design of second-generation agents, and evaluate their potential as noninvasive diagnostic agents in biochemical systems, mouse models, and human tissues. We also propose to critically evaluate the potential of these 99m Tc-peptides to detect in vivo A¿ plaques in APPsw+/- transgenic mice versus control mice using our multiplexed multi-pinhole NanoSPECT/CT imaging system; perform complete pharmacokinetic analysis in animal models; and investigate mechanism(s) involved in uptake of our agent into the brain via multiple bioassays. These novel imaging agents may enable noninvasive SPECT imaging of A¿ in patients and assist analysis of the efficacy of new molecular-targeted therapies in AD. . Discovery of diagnostic agents capable of detecting early stages of Alzheimer's Disease (AD) would assist in disease management as well as aid in the evaluation of therapeutics under development to inhibit or reverse formation of A¿ plaques in patients. Towards this objective, the proposed project involves further characterization of a lead agent in diseased and control animal models and is based upon a strategy with potential for widespread deployment of a cost- efficient test for early diagnosis of AD.

描述(申请人提供)：一种在体内检测和量化淀粉样斑块(A)的非侵入性方法将在阿尔茨海默病(AD)的死前诊断和监测抗淀粉样蛋白治疗方面具有广泛的实用价值。虽然几种基于PET的显像剂正在开发中，但一种易于获取、高效和高度特异的基于~(99)Tm的SPECT显像剂将是非常理想的。在探索基于多肽的生物医学应用时，我们发现了一种小肽，它含有医学成像中最常用的同位素--~(99)Tm。我们的99mTc-肽以浓度依赖和饱和的方式与Aβ特异性结合。在APPsw+/-转基因小鼠的脑部切片中，该试剂仍未被代谢，而且该先导试剂的荧光类似物显示出A？斑块的染色，而在年龄匹配的WT对照组中则没有。重要的是，尾静脉注射99mTC多肽2小时后，APPsw+/-转基因小鼠和年龄匹配的对照组的冰冻脑切片的磷成像显示，APPsw+/-小鼠选择性地保留了放射性示踪剂，而对照组只有背景结合。我们现在建议评估不同的螯合核心对我们的先导剂靶向性的影响，以确定指导第二代试剂设计的结构-活性关系，并评估它们作为生化系统、小鼠模型和人类组织的非侵入性诊断试剂的潜力。我们还建议使用我们的多路多针孔纳米SPECT/CT成像系统，严格评估这些99mTc多肽在APPsw+/-转基因小鼠和对照小鼠体内检测A？斑块的潜力；在动物模型中进行完整的药代动力学分析；并通过多种生物检测方法研究我们的制剂在大脑中摄取的机制(S)。这些新的显像剂可以实现对患者的非侵入性SPECT成像，并辅助分析新的分子靶向治疗AD的疗效。。发现能够检测阿尔茨海默病(AD)早期阶段的诊断试剂将有助于疾病管理，并有助于评估正在开发的抑制或逆转患者A型斑块形成的疗法。为实现这一目标，拟议的项目涉及在疾病和对照动物模型中进一步确定先导剂的特征，并基于一项有可能广泛应用具有成本效益的测试以早期诊断AD的战略。