Metal-Mediated C-H Radiofluorination for Rapid Access to PET Imaging Agents

金属介导的 C-H 放射性氟化用于快速获得 PET 成像剂

• 批准号: 10615600
• 负责人: Jay Samuel Wright
• 金额: $ 7.81万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10615600
• 关键词: Acids; Adoption; Agrochemicals; Amidines; Amines; Antimalarials; Biotechnology; Chemistry; Chloroquine; Clinical; Clinical Trials; Copper; Data; Detection; Development; Diagnostic; Discipline; Disease; Disease Progression; Drug Costs; Drug Industry; Drug Targeting; Elements; Environment; Financial cost; Fluorides; Fluorine; Goals; Grant; Healthcare; Human; Hydrogen Bonding; Image; Image Enhancement; Imaging Techniques; Institution; Interdisciplinary Study; Knowledge; Label; Laboratories; Libraries; Ligands; Manuals; Marketing; Mediating; Medicine; Mentors; Metals; Methodology; Methods; Michigan; Mission; Modeling; Monitor; National Institute of Biomedical Imaging and Bioengineering; Organometallic Chemistry; Oxides; Periodicals; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Population; Positioning Attribute; Positron-Emission Tomography; Preparation; Procedures; Process; Production; Property; Protocols documentation; Quinine; Radio; Radioactive; Radiochemistry; Radioisotopes; Radiolabeled; Radiology Specialty; Radiopharmaceuticals; Rationalization; Reaction; Research; Research Design; Research Proposals; Role; Salts; Scanning; Silver; Silver Compounds; Sodium Chloride; Tracer; Training; Translating; Universities; Validation; Vitamin B6; analog; bioactive scaffold; bioimaging; cancer imaging; career; career development; clinical translation; cost; design; disease diagnostic; disorder prevention; drug development; drug discovery; experience; experimental study; imaging agent; imaging modality; imaging study; improved; innovation; invention; neuroimaging; novel; novel therapeutics; nuclear imaging; oxidation; patient population; pharmacologic; protocol development; quinoline; scaffold; screening; skills; stable isotope; translational study

Project Summary/Abstract Fluorine is an essential constituent of many commercial molecules, including (radio)pharmaceuticals, agrochemicals, and functional materials. Fluorine-19 (stable isotope) is routinely introduced into aromatic pharmaceuticals in order to modulate pharmacological properties. Many positron emission tomography aromatic (PET) imaging agents are labeled with fluorine-18 (radioactive isotope) for studying and monitoring disease, as well as evaluating drug-target engagements and enriching clinical trials. Considerable progress has been made in the development of aromatic fluorine-18 imaging agents for these applications, although more robust radiosyntheses are required to support and expedite tracer discovery and meet the increasing demand for radiopharmaceuticals from the healthcare and pharmaceutical industries. The primary aim of this project is to overcome challenges associated with radiofluorination through the invention of radiosynthetic methods that support the design of aromatic PET imaging agents. Specifically, the central claim is that radiofluorinated organic molecules can be accessed by designing silver- and copper-containing species competent in C-H radiofluorination. Copper is an abundant and inexpensive element that has previously been shown to (radio)fluorinate aromatic C-H bonds, albeit with a limited scope. Silver resides in the same periodic group as copper and preliminary data suggests that it can induce C-H radiofluorination transformations. To achieve these goals, the proposal is divided into three aims: Aim 1 is to use fluorine-18 labeled silver compounds for the radiofluorination of organic molecules. Aim 2 is to utilize this method for the automated radiosynthesis of fluorine- 18 labeled bioactive molecules Aim 3 is to develop new copper-mediated C-H functionalization methodologies for the direct, automated fluorine-18 labeling of aromatic bioactive molecules. Ultimately, enhancement of this imaging modality as described in this grant is expected to fundamentally alter the current radiosynthetic paradigm and expedite aromatic radiofluorination, providing new and rapid access to fluorine-18 labeled pharmaceuticals used in PET. Importantly, developments in PET biotechnology are continually being used to fundamentally improve the detection, treatment, and prevention of disease, consistent with the mission of NIBIB. This grant builds on the ongoing multidisciplinary collaboration between Prof Peter J. H. Scott (Department of Radiology) and Prof Melanie S. Sanford (Department of Chemistry), which focuses on the development of radiosynthetic methods at the University of Michigan. The facilities and faulty/staff expertise offered in these laboratories provide an outstanding research environment that will facilitate the candidate's acquisition of further skills necessary for gaining an academic position at a US institution, consistent with his long-term career goal. In particular, this project will provide new opportunities to merge radiochemistry and organometallic chemistry, which will serve the candidate's career development toward a professorship in chemistry with a focus on C-H radiolabeling for PET applications.

项目摘要/摘要 氟是许多商业分子的基本成分，包括(放射性)药物， 农用化学品和功能材料。氟-19(稳定同位素)通常被引入芳香族化合物 药物，以调节药理特性。多正电子发射断层扫描芳香族 (PET)显像剂被标记有氟-18(放射性同位素)，用于研究和监测疾病，如 以及评估药物靶标的参与度和丰富临床试验。已经取得了相当大的进展 在开发用于这些应用的芳香族氟-18显像剂方面，尽管更强大 需要放射性合成来支持和加速示踪剂的发现，并满足日益增长的 来自医疗保健和制药行业的放射性药品。这个项目的主要目的是 通过发明放射性合成方法克服与放射性氟化相关的挑战 支持芳香族PET显像剂的设计。具体地说，中心主张是放射性氟化有机物质 分子可以通过设计具有C-H活性的含银和含铜的物种来获得 放射性氟化。铜是一种储量丰富且价格低廉的元素，此前已被证明 (放射性)氟化芳香族C-H键，尽管范围有限。银位于相同的周期组中，与 铜和初步数据表明，它可以诱导C-H放射性氟化转化。要实现这些目标 目标，该提案分为三个目标：目标1是将氟-18标记的银化合物用于 有机分子的放射性氟化。目标2是利用这种方法进行氟的自动放射合成- 18标记生物活性分子的目标3是开发新的铜介导的C-H功能化方法 用于芳香族生物活性分子的直接、自动化的氟-18标记。最终，这一点的增强 这项资助中描述的成像方式有望从根本上改变目前的放射合成范例。 和加快芳香族放射性氟化，提供新的和快速的氟-18标记药物 用于聚酯。重要的是，PET生物技术的发展不断被用来从根本上 改进疾病的检测、治疗和预防，与NIBIB的使命一致。这笔赠款 建立在彼得·J·H·斯科特教授(放射科)之间持续的多学科合作基础上 梅勒妮·S·桑福德教授(化学系)，专注于放射合成的发展 方法在密歇根大学。这些实验室提供的设施和有问题的/工作人员的专业知识 提供一个出色的研究环境，以促进候选人获得进一步的技能 在美国机构获得学术职位所必需的，这与他的长期职业目标是一致的。在……里面 特别是，这个项目将为放射化学和有机金属化学的融合提供新的机会， 这将有助于候选人的职业发展，成为化学教授，重点是C-H PET应用的放射性标记。