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有机磷酸盐（OP）神经毒剂是一个紧迫的问题，并促使新的调查，以开发治疗方法，以打击人类接触。这些研究工作正在产生新的方法和小分子发现，以抵消OP中毒，接近初步的翻译应用。我们的长期目标是开发翻译检测，通过采用正电子发射断层扫描（PET）成像，随时间推移在活体受试者中评价、测量和验证新的OP治疗药物。PET成像允许在存在和不存在治疗性治疗和解毒剂的情况下评估关键药代动力学（PK）和药效学（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，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）高纯度特异性AEP衍生物，通过评价抗胆碱酯酶活性和机制，证明它们的作用与OP神经毒剂相似，并对其抑制性抗胆碱酯酶活性特征进行排名。目标二：选择前五名的目标1候选剂（抑制剂ki值e 104 M-1 min-1），并制备其正电子标记的碳-11和氟-18前体。目的3：制备5种~（11）C和~（18）F标记的AMP抑制剂示踪剂（放化产率e10%，高比活度）。目标4：在啮齿动物受试者中使用microPET-CT-MR成像评价Aim 3示踪剂的CNS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）质量对示踪剂进行分级（摄取，最大值和洗脱），然后选择3个最佳示踪剂（渗透率e 1%注射剂量和TAC显示为在正电子放射性标记的4-5个半衰期内的最大值和初始洗脱期）以推进至目标5。目标5：通过识别三种Aim 4示踪剂中的哪一种适合于通过进行离散示踪剂PD microPET成像实验来进行推进，该实验与选定的已知OP药剂共同给药，包括已确定的：a）OP抑制剂对氧磷，和B）OP中毒解毒剂治疗，2-吡啶醛肟甲碘化物（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，这些武器的生产和部署相对便宜。本研究的相关性是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，并用于验证和评估新的治疗药物和方法，用于在发生攻击时的临床应用。

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.