Molecular Imaging of Chemical Threats and Countermeasures

化学威胁的分子成像及对策

基本信息

批准号：
9113105
负责人：
JOHN M GERDES
金额：
$ 71.71万
依托单位：
UNIVERSITY OF MONTANA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9113105
关键词：
Accounting Ache Aging Animal Model Animals Antidotes Benchmarking Biodistribution Biological Assay Cations Cavia Charge Chemical Weapons Chemicals Clinical Data Development Diagnostic Drug Kinetics Enzymes Event Exhibits Fluorine Functional Imaging Goals Government Agencies Health Image Imaging Device Investigation Kinetics Label Life Macaca mulatta Measures Methods Military Personnel Molecular Nerve Tissue Organophosphates Oximes Paraoxon Performance Peripheral Pharmaceutical Preparations Pharmacodynamics Pharmacology Phase Poisoning Positron Positron-Emission Tomography Primates Process Property Rattus Recovery Reporter Reporting Research Research Personnel Rodent Sarin Staging Structure Terrorism Therapeutic Therapeutic Agents Time Tissue imaging Tissues Tracer Variant Visual adduct analog base combat comparative design imaging agent imaging platform in vivo in vivo imaging inhibitor/antagonist insight methylphosphonate molecular imaging nerve agent neurotoxicity nonhuman primate novel novel strategies novel therapeutics quantitative imaging radioligand

项目摘要

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.

描述（由适用提供）：恐怖分子，流氓组织或政府机构可能部署有机磷酸盐（OP）神经毒剂是直接关注的，并且促使新的投资更好地了解OP代理的特性，以便可以开发出新的治疗方法来打击和反复OPS的不良影响。这些研究努力正在产生新的方法和分子对策，以改善与OP相关的短期和长期神经毒性。本应用程序中的对象是：（1）在大鼠，豚鼠和灵长类动物中提供三种OP结构类型（VX，Sarin和Paraoxon）暴露的定量和视觉记载，以促进我们对OP生物分布的理解；（2）在大鼠，豚鼠和灵长类动物中提供三种氧气亚型（阳离子，中性和骨）的定量和视觉记载，以促进我们对氧生物分布的理解；（c）开发新的动态测定方法，通过采用极性发射断层扫描（PET）成像，随着时间的推移评估，测量和验证现场受试者中的新治疗剂。该方法将评估关键的药代动力学（PK）和药效学（PD）参数，因此，该应用将生成新的18F和11C标记的有机磷酸盐和氧气PET成像示踪剂，以证明其在实时啮齿动物/灵活的主题中的功能成像实用性，并在特定在场的情况下验证其性能质量。为了实现这些目标，将准备合理设计的甲基膦酸酯PET放射线，以以下由两个操作阶段定义的渐进特定目标：I期（特定目标1-2）。 OP和对策宠物成像示踪剂和II期的设计和合成（特定目的3-6）。建立并确认对立分子成像动物平台。具体目的1和2将综合并验证18F和11C标记的OP和Oximes Tracers的作用机理和药理机理。具体目的3-4将确定大鼠和豚鼠中18F和11C标记的OP和Oximes示踪剂的PK/PD轮廓。具体目的5-6将推进实验，以进行组合方法，并评估18F和11C标记的示踪剂的诊断能力，并在非人类隐私中使用候选OP和氧气示踪剂。特定目标3-6将在每个物种中集体负担成像平台。