In Vivo Pharmacokinetic and Pharmacodynamic Dispositions of Positron Radiolabeled

描述（由申请人提供）：在恐怖行动中可能部署的有机磷（OP）神经毒剂是迫在眉睫的问题，并促使新的研究开发治疗方法来对抗人类暴露。这些研究努力正在产生对抗OP中毒的新方法和小分子发现，这些方法和小分子发现已接近初步的转化应用。我们的长期目标是通过正电子发射断层扫描（PET）成像，开发一种转化分析方法，随着时间的推移，评估、测量和验证新的OP治疗剂。PET成像允许评估关键药代动力学（PK）和药效学（PD）参数在治疗和解毒剂的存在和不存在。因此，本应用程序的目标是建立新的OP PET成像示踪剂，展示其在活体啮齿动物受试者中的初始功能成像效用，并在存在特定对策治疗的情况下初步验证其性能质量。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甲基膦酸烷氧基（AMP）和2-甲氧基乙基膦酸酯（EMP）放射性配体，具有以下五个渐进和协作的具体目标：制备10种非放射性（冷）高纯度特异性AEP衍生物，通过评价其抗胆碱酯酶活性和机制，证明其与OP神经毒剂的作用相似，并对其抑制抗胆碱酯酶活性谱进行排序。Aim 2：选择前5名Aim 1候选药物（抑制剂ki值为104 M-1min-1）并制备其正电子标记碳-11和氟- 18前体。目标3：生产五种碳-11和氟-18放射性标记的AMP抑制剂示踪剂（放射化学产率为10%，高比活性）。目的4：用微pet - ct - mr成像评估Aim 3示踪剂在啮齿动物体内的中枢神经系统组织PK质量，将示踪剂作为特定组织示踪剂渗透和相关时间-活性曲线（TAC）质量（吸收、最大值和洗脱）的函数进行排名，然后选择3种最佳示踪剂（渗透1%注射剂量和TAC在正电子放射性标记的4-5半衰期内显示最大值和初始洗脱期），进入Aim 5。目标5：通过进行离散示踪剂PD微pet成像实验，确定三种Aim 4示踪剂中哪一种适合推进，建立翻译概念验证，该实验与选择已知的OP药物共同施用，包括既定的：a) OP抑制剂对氧磷，和b) OP中毒解毒剂治疗，2-吡啶醛肟甲氧嘧啶（2-PAM）。

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.