In Vivo Pharmacokinetic and Pharmacodynamic Dispositions of Positron Radiolabeled

正电子放射性标记的体内药代动力学和药效学分布

基本信息

批准号：
8020760
负责人：
JOHN M GERDES
金额：
$ 35.47万
依托单位：
UNIVERSITY OF MONTANA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-30 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8020760
关键词：
Acute Address Antidotes Attention Biological Biological Assay Carbon Cholinesterase Inhibitors Clinical Development Dose Drug Kinetics Event Exposure to Fluorine Functional Imaging Goals Half-Life Image Insecticides Investigation Label Life Magnetic Resonance Imaging Measures Methodology Military Personnel Modality Neuraxis Organ Organophosphates Paraoxon Penetration Performance Peripheral Pharmaceutical Preparations Pharmacodynamics Phase Poison Positron Positron-Emission Tomography Primates Property Protocols documentation Radioactive Radioisotopes Radiolabeled Research Rodent Structure Technology Terrorism Therapeutic Therapeutic Agents Time Tissues Toxic Actions Toxic effect Tracer United States United States National Institutes of Health base combat design exposed human population imaging modality in vivo inhibitor/antagonist insight methylphosphonate nerve agent neurotoxic novel novel strategies novel therapeutics organophosphate poisoning phosphonate preclinical study programs pyridine radiochemical radioligand radiotracer research study small molecule success toxic organophosphate insecticide exposure uptake weapons

项目摘要

DESCRIPTION (provided by applicant): The possible deployment of organophosphate (OP) nerve agents in terrorist actions is of immediate concern and has prompted new investigations to develop therapeutics to combat human exposures. These research endeavors are producing new approaches and small molecule discoveries to counteract OP poisoning that are nearing initial translational applications. Our long-term objective is to develop translational assays that evaluate, measure and validate new OP therapeutic agents in live subjects over time by employing positron emission tomography (PET) imaging. PET imaging allows the assessment of key pharmacokinetic (PK) and pharmacodynamic (PD) parameters in the presence and absence of therapeutic treatments and antidote agents. Thus, the goal of this application is to establish new OP PET imaging tracers, to demonstrate their initial functional imaging utility in live rodent subjects, and to initially validate their performance qualities in the presence of specific countermeasure treatments. To satisfy this goal we will establish requisite OP PET imaging tracers using a logical discovery paradigm that will advance rationally designed alkoxy methylphosphonate (AMP) and ethyl 2-methoxyethyl phosphonates (EMP) radioligands with the following five progressive and collaborative specific aims: Aim 1: Prepare 10 non-radioactive (cold) high purity specific AEP derivatives, demonstrate they act similarly to OP nerve agents by evaluating the anti-cholinesterase activity and mechanism, and rank their inhibitory anti-cholinesterase activity profiles. Aim 2: Select the top five Aim 1 candidate agents (inhibitor ki values e 104 M-1min-1) and prepare their positron labeling carbon-11 and fluorine- 18 precursors. Aim 3: Produce five carbon-11 and fluorine-18 radiolabeled AMP inhibitor tracers (radiochemical yields e 10 %, high specific activity). Aim 4: Evaluate CNS tissue PK qualities of the Aim 3 tracers with microPET-CT-MR imaging in rodent subjects, rank the tracers as a function of specific tissue tracer penetration and cognate time-activity curve (TAC) qualities (uptake, maximum and washout) then select the 3 best tracers (penetration e 1 % injected dose and TACs shown with maximums and initial washout phases within 4-5 half-lives of the positron radiolabel) to advance to Aim 5. Aim 5: Establish translational proof-of-concept by discerning which of the three Aim 4 tracers are suitable for advancement by performing discrete tracer PD microPET imaging experiments carried out with the co-administration of select known OP agents, including the established: a) OP inhibitor paraoxon, and b) OP poisoning antidote treatment, 2-pyridine aldoxime methiodide (2-PAM). PUBLIC HEALTH RELEVANCE: The United States remain vulnerable to acts of terrorism using unconventional weapons including highly toxic chemical nerve agents like organophosphates, which are relatively inexpensive to produce and deploy in an attack on civilians. The relevance of this investigation is to develop novel positron emission tomography (PET) tissue imaging agents based on organophosphate structure to be used to demonstrate the in vivo action and distribution of organophosphates, and serve to validating and assess new therapeutic drugs and approaches for clinical use in the event of an attack.

描述（由申请人提供）：在恐怖活动中可能使用有机磷（OP）神经毒剂引起了人们的直接关注，并促使人们进行新的调查以开发治疗方法来对抗人类暴露。这些研究工作正在产生新的方法和小分子发现来对抗OP中毒，这些方法和小分子已经接近初步的转化应用。我们的长期目标是开发转化检测方法，通过采用正电子发射断层扫描 (PET) 成像，随着时间的推移在活体受试者中评估、测量和验证新的 OP 治疗剂。 PET 成像可以在存在或不存在治疗方法和解毒剂的情况下评估关键药代动力学 (PK) 和药效 (PD) 参数。因此，本申请的目标是建立新的 OP PET 成像示踪剂，以证明其在活体啮齿动物受试者中的初始功能成像效用，并初步验证其在特定对策治疗中的性能质量。为了实现这一目标，我们将使用逻辑发现范式建立必要的 OP PET 成像示踪剂，该范式将推进合理设计的烷氧基甲基膦酸酯 (AMP) 和乙基 2-甲氧基乙基膦酸酯 (EMP) 放射性配体，并具有以下五个渐进和协作的具体目标：目标 1：制备 10 种非放射性（冷）高纯度特定 AEP 衍生物，通过评估抗胆碱酯酶活性和机制来证明它们与 OP 神经毒剂的作用相似，并对它们进行排名抑制性抗胆碱酯酶活性谱。目标 2：选择前 5 个目标 1 候选试剂（抑制剂 ki 值 e 104 M-1min-1）并制备其正电子标记碳 11 和氟 18 前体。目标 3：产生五种碳 11 和氟 18 放射性标记的 AMP 抑制剂示踪剂（放射化学产率 10%，高比活度）。目标 4：在啮齿动物受试者中使用 microPET-CT-MR 成像评估 Aim 3 示踪剂的中枢神经系统组织 PK 质量，根据特定组织示踪剂渗透和同源时间活性曲线 (TAC) 质量（摄取、最大和冲洗），然后选择 3 个最佳示踪剂（注射剂量为 1% 的渗透率和 TAC，显示最大值和初始冲洗阶段在正电子的 4-5 个半衰期内radiolabel）推进到目标 5。目标 5：通过与选定的已知 OP 共同施用进行离散示踪剂 PD microPET 成像实验，辨别三种 Aim 4 示踪剂中哪一种适合推进，建立转化概念验证药物，包括已建立的：a) OP 抑制剂对氧磷，和 b) OP 中毒解毒剂治疗，2-吡啶醛肟甲硫氨酸 (2-PAM)。公共卫生相关性：美国仍然容易受到使用非常规武器的恐怖主义行为的影响，包括有机磷酸盐等剧毒化学神经毒剂，这些毒剂的生产和部署成本相对较低，用于攻击平民。本研究的意义在于开发基于有机磷酸酯结构的新型正电子发射断层扫描（PET）组织成像剂，用于证明有机磷酸酯的体内作用和分布，并用于验证和评估临床使用的新治疗药物和方法如果发生攻击。