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

描述（由申请人提供）：一种在体内检测和定量-淀粉样蛋白斑块（A¿）的无创方法将广泛应用于阿尔茨海默病（AD）的死前诊断和抗淀粉样蛋白治疗的监测。虽然几种基于pet的显像剂正在开发中，但一种易于获取，高效且高度特异性的技术-基于99m的SPECT显像剂将是非常可取的。在探索生物医学应用的肽类药物时，我们发现了一种小肽，可以容纳锝-99m，这是医学成像中最常用的同位素。我们的铅99mtc肽以浓度依赖和饱和的方式特异性地与A¿结合。该药物仍未被代谢，铅剂的荧光类似物显示APPsw+/-转基因小鼠的脑切片中有a¿斑块的染色，而在年龄匹配的WT对照组中没有。重要的是，在尾静脉注射99mtc肽2小时后，对APPsw+/-转基因小鼠和年龄匹配的对照组冷冻脑切片的磷成像显示，APPsw+/-小鼠的放射性示踪剂选择性保留，而对照组只有背景结合。我们现在建议评估各种螯合核心对我们的先导药物靶向特性的影响，以定义指导第二代药物设计的结构-活性关系，并评估它们在生化系统、小鼠模型和人体组织中作为非侵入性诊断药物的潜力。我们还建议使用我们的多路多针孔NanoSPECT/CT成像系统，严格评估这些99m tc -肽在APPsw+/-转基因小鼠与对照小鼠体内检测A¿斑块的潜力；进行完整的动物模型药代动力学分析；并通过多种生物测定研究我们的药物进入大脑的机制。这些新型显像剂可以对患者进行无创SPECT成像，并有助于分析新的AD分子靶向治疗的疗效。发现能够检测早期阿尔茨海默病（AD）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¿斑块形成的治疗方法。为了实现这一目标，拟议的项目涉及在患病和对照动物模型中进一步表征一种先导剂，并基于一种有可能广泛部署一种具有成本效益的阿尔茨海默病早期诊断测试的策略。

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.