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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.