Molecular Imaging of Chemical Threats and Countermeasures

 描述(申请人提供)：恐怖分子、流氓组织或政府机构可能使用有机磷(OP)神经毒剂，这是一个直接令人关注的问题，并已促使新的调查，以更好地了解OP毒剂的特性，以便开发新的疗法来对抗和逆转OP的不良影响。这些研究努力正在产生新的方法和分子对策来改善与OP相关的短期和长期神经毒性。本应用的目标是：(1)提供三种OP结构类型(VX，沙林和对氧磷)在大鼠、豚鼠和灵长类动物中暴露的定量和可视化描述，以促进我们对OP生物分布的了解；(2)提供三种肟亚型(阳离子、中性和两性离子)在大鼠、豚鼠和灵长类动物中的定量和可视化描述，以促进我们对肟类生物分布的了解；以及(C)建立新的动态分析方法，通过使用正电子发射断层扫描(PET)成像来评估、测量和验证新的治疗药物在活体受试者中的分布。该方法将评估关键的药代动力学(PK)和药效学(PD)参数，因此，这一应用将产生新的18F和11C标记的有机磷和肟PET成像示踪剂，以展示它们在活体啮齿动物/灵长类受试者中的功能成像用途，并在存在特定对策的情况下验证它们的性能质量。为了实现这些目标，将通过两个操作阶段定义以下渐进的具体目标来制备合理设计的甲基膦酸酯PET放射性配基：第一阶段(具体目标1-2)。OP和对策PET成像示踪剂和第二阶段的设计和合成(具体目标3-6)。建立和确认分子成像动物平台的对策。特定的目标1和2将合成和验证18F和11C标记的OP和肟类示踪剂的作用机制和药理学。特定的AIMS 3-4将确定18F和11C标记的OP和肟示踪剂在大鼠和豚鼠中的PK/PD谱。特定的AIMS 5-6将把实验推进到组合方法，评估18F和11C标记示踪剂的诊断能力，并在非人类灵长类动物中使用候选OP和肟示踪剂。特定目标3-6将共同提供每个物种的成像平台。

 DESCRIPTION (provided by applicant): The possible deployment of organophosphate (OP) nerve agents by terrorists, rogue organizations, or by government agencies is of immediate concern and has prompted new investigations to better understand the properties of OP agents so that new therapeutics can be developed to combat and reverse the ill effects of OPs. These research endeavors are producing new approaches and molecular countermeasures to ameliorate the short- and long-term neurotoxicity associated with OPs. The objectives in this application are: (1) to provide quantitative and visual accounts of three OP structure types (VX, sarin and paraoxon) exposures in rats, guinea pigs and primates to advance our understanding of OP biodistribution; and (2) to provide quantitative and visual accounts of three oxime subtypes (cation, neutral and zwitterion) in rats, guinea pigs and primates to advance our understanding of oxime biodistribution; and (c) to develop new dynamic assays that evaluate, measure and validate new therapeutic agents in live subjects over time by employing positron emission tomography (PET) imaging. The approach will assess key pharmacokinetic (PK) and pharmacodynamic (PD) parameters and thus, this application will generate new 18F- and 11C-labeled organophosphate and oxime PET imaging tracers to demonstrate their functional imaging utility in live rodent/primate subjects, and validate their performance qualities in the presence of specific countermeasures. To accomplish these goals, rationally designed methylphosphonate PET radioligands will be prepared with the following progressive specific aims defined by two operational phases: Phase I (Specific Aims 1-2). Design and Synthesis of OP and Countermeasure PET Imaging Tracers and Phase II (Specific Aims 3-6). Establish and Confirm the Countermeasure Molecular Imaging Animal Platforms. Specific aims 1 and 2 will synthesize and validate the mechanism of action and pharmacology of the 18F- and 11C-labeled OP and oximes tracers. Specific Aims 3-4 will determine the PK/PD profiles of the 18F- and 11C-labeled OP and oxime tracers in rat and guinea pig. Specific aims 5-6 will advance the experimentation to combination approaches and evaluate the diagnostic capabilities of the 18F- and 11C-labeled tracers and use a candidate OP and oxime tracer in non-human primates. Specific aims 3-6 will collectively afford imaging platforms in each species.