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

描述（由申请人提供）：一种用于体内检测和定量淀粉样蛋白斑块（A）的非侵入性方法将广泛用于阿尔茨海默病（AD）的生前诊断和监测抗淀粉样蛋白治疗。虽然几种基于PET的试剂正在开发中，但非常需要一种容易获得的、有效的和高度特异性的基于锝-99m的SPECT成像剂。在探索用于生物医学应用的肽基试剂时，我们发现了一种小肽，可容纳锝-99m，这是医学成像中最常用的同位素。我们的前导99 mTc-肽以浓度依赖性和饱和的方式特异性结合A？。该药物保持未代谢状态，并且先导药物的荧光类似物显示APPsw+/-转基因小鼠脑切片中A？斑块染色，而在其年龄匹配的WT对照组中无A？斑块。重要的是，尾静脉注射99 mTc-肽后2小时，APPsw+/-转基因小鼠和年龄匹配的对照的冷冻脑切片的磷光成像证明了APPsw+/-小鼠中放射性示踪剂的选择性保留和对照中仅背景结合。我们现在建议评估各种螯合核心对我们的主导剂的靶向性质的影响，以定义指导第二代试剂设计的结构-活性关系，并评估其作为生化系统，小鼠模型和人体组织中的非侵入性诊断试剂的潜力。我们还建议使用我们的多路复用多针孔NanoSPECT/CT成像系统来严格评估这些99 m Tc-肽检测APPsw+/-转基因小鼠与对照小鼠中体内A？斑块的潜力;在动物模型中进行完整的药代动力学分析;并通过多种生物测定来研究我们的药剂摄取到大脑中所涉及的机制。这些新的显像剂可能使非侵入性SPECT成像的A ²患者和辅助分析的疗效，新的分子靶向治疗AD。.发现能够检测阿尔茨海默病（AD）早期阶段的诊断剂将有助于疾病管理，并有助于评估正在开发的治疗方法，以抑制或逆转患者中A斑块的形成。为了实现这一目标，拟议的项目涉及进一步表征患病和对照动物模型中的主要药物，并基于一种可能广泛部署用于AD早期诊断的具有成本效益的检测方法的策略。

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.