Molecular Imaging of Chemical Threats and Countermeasures

化学威胁的分子成像及对策

• 批准号: 9760008
• 负责人: JOHN M GERDES
• 金额: $ 80.26万
• 依托单位: UNIVERSITY OF MONTANA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9760008
• 关键词: 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; Imaging Device; Investigation; Kinetics; Label; Macaca mulatta; Measures; Methods; Military Personnel; Molecular; Nerve Tissue; Organophosphates; Oximes; Paraoxon; Performance; Peripheral; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacology and Toxicology; Phase; Poisoning; Positron; Positron-Emission Tomography; Primates; Process; Property; Rattus; Recovery; Reporter; Reporting; Research; Research Personnel; Rodent; Sarin; Structure; Terrorism; Therapeutic; Therapeutic Agents; Time; Tissue imaging; Tissues; Tracer; Variant; Visual; adduct; analog; animal imaging; base; chemical countermeasure; chemical threat; 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; pharmacokinetics and pharmacodynamics; public health relevance; quantitative imaging; radioligand

 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酸酯 (OP) 神经毒剂，这一点值得立即关注，并促使开展新的调查，以更好地了解 OP 毒剂的特性，以便可以开发新的治疗方法。这些研究工作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。 (1) 提供大鼠、豚鼠和灵长类动物中三种 OP 结构类型（VX、沙林和对氧磷）暴露的定量和可视化说明，以增进我们对 OP 生物分布的理解；以及 (2) 提供三种肟的定量和可视化说明；大鼠、豚鼠和灵长类动物的亚型（阳离子、中性和两性离子），以增进我们对肟生物分布的理解；(c) 开发新的动态测定法来评估、测量随着时间的推移，通过采用正电子发射断层扫描 (PET) 成像在活体受试者中验证新的治疗药物，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。和肟 PET 成像示踪剂，以在活体啮齿动物/灵长类动物受试者中展示其功能成像实用性，并在存在特定对策的情况下验证其性能质量。为了实现这些目标，合理设计了膦酸甲酯 PET。放射性配体将按照两个操作阶段定义的以下渐进具体目标进行准备：第一阶段（OP 和对策 PET 成像示踪剂的设计和合成）和第二阶段（具体目标建立和确认）。对策分子成像动物平台的具体目标1和2将综合并验证18F和11C标记的作用机制和药理学。 OP 和肟示踪剂。具体目标 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 曲线。具体目标 5-6 将推进组合方法的实验并评估。 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。 具体目标 3-6 将。共同提供每个物种的成像平台。

项目成果

The inhibition, reactivation and mechanism of VX-, sarin-, fluoro-VX and fluoro-sarin surrogates following their interaction with HuAChE and HuBuChE.

• DOI: 10.1016/j.cbi.2018.06.019
• 发表时间: 2018-08-01
• 期刊: Chemico-biological interactions
• 影响因子: 5.1
• 作者: Chao CK;Balasubramanian N;Gerdes JM;Thompson CM
• 通讯作者: Thompson CM

Biological Distribution and Metabolic Profiles of Carbon-11 and Fluorine-18 Tracers of VX- and Sarin-Analogs in Sprague-Dawley Rats.

• DOI: 10.1021/acs.chemrestox.0c00237
• 发表时间: 2021-01-18
• 期刊: Chemical research in toxicology
• 影响因子: 4.1
• 作者: Hayes TR;Chao CK;Blecha JE;Huynh TL;Zinn KR;Thompson CM;Gerdes JM;VanBrocklin HF
• 通讯作者: VanBrocklin HF

Radiosynthesis, ex Vivo Biodistribution, and in Vivo Positron Emission Tomography Imaging Evaluations of [11C]2-Pyridinealdoxime Methiodide ([11C]2-PAM): A First-In-Class Antidote Tracer for Organophosphate Intoxication.

[11C]2-吡啶醛肟甲硫醚 ([11C]2-PAM) 的放射合成、离体生物分布和体内正电子发射断层扫描成像评估：一种用于有机磷中毒的一流解毒示踪剂。

• DOI: 10.1021/acschemneuro.8b00212
• 发表时间: 2018
• 期刊: ACS chemical neuroscience
• 影响因子: 5
• 作者: Neumann,KielD;Blecha,JosephE;Hayes,ThomasR;Huynh,Tony;Chao,Chih-Kai;Guilloteau,Nicolas;Zinn,KurtR;VanBrocklin,HenryF;Thompson,CharlesM;Gerdes,JohnM
• 通讯作者: Gerdes,JohnM

Inhibition of Acetylcholinesterases by Stereoisomeric Organophosphorus Compounds Containing Both Thioester and p-Nitrophenyl Leaving Groups.

含有硫酯和对硝基苯基离去基团的立体异构有机磷化合物对乙酰胆碱酯酶的抑制。

• DOI: 10.1021/acs.chemrestox.0c00236
• 发表时间: 2020
• 期刊: Chemical research in toxicology
• 影响因子: 4.1
• 作者: Talley,ToddT;Chao,Chih-Kai;Berkman,CliffordE;Richardson,RudyJ;Thompson,CharlesM
• 通讯作者: Thompson,CharlesM