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

• 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
• 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

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）：在恐怖行动中可能部署有机磷酸盐（OP）神经因素是直接关注的，并且促使新的调查开发了与人类暴露的治疗方法。这些研究努力正在产生新的方法和小分子发现，以抵消接近初始转化应用的OP中毒。我们的长期目标是开发转化测定法，通过采用正电子发射断层扫描（PET）成像来评估，衡量和验证现场受试者中新的OP治疗剂。 PET成像允许在存在和不存在治疗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，该应用的目的是建立新的OP PET成像示踪剂，以实现活啮齿动物受试者中的最初功能成像实用性，并在存在特定的对策处理的情况下最初验证其性能质量。 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通过评估抗胆碱酯酶活性和机制，并对其抑制性抗胆碱酯酶活性谱进行评估。 AIM 2：选择前五名AIM 1候选剂（抑制剂Ki值E 104 M-1MIN-1），然后准备其正电子标记碳11和氟-18前体。 AIM 3：生产五个碳11和氟-18放射性标记的AMP抑制剂示踪剂（放射化学产量E 10％，高特异性活性）。 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正电子放射线标线的半衰期）要晋升为目标5。目标5：通过确定三个目标中的哪个示踪剂中的哪个适合通过执行离散的示踪剂PD MicroPET成像实验，适合于进行进步，并与既定的Opine op pare and op pare and pare and ap pare and ap pare and ape in ap pare and a a op para and themiby and para”醛虫甲氧基（2-PAM）。 公共卫生相关性：美国仍然容易采用恐怖主义行为，其中包括高毒性化学神经剂等非常规武器，例如有机磷酸盐，它们相对便宜地生产和部署对平民的袭击。这项研究的相关性是开发基于有机磷酸盐结构的新型正电子发射断层扫描（PET）组织成像剂，用于证明有机磷酸盐的体内作用和分布，并用于验证和评估新的治疗药物，并在发作时临床使用。