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

基本信息

批准号：
10369752
负责人：
Jay Samuel Wright
金额：
$ 8万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
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/10369752
关键词：
2-arachidonylglycerol 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 Industry Human Hydrogen Bonding Image Image Enhancement Imaging Techniques Institution Interdisciplinary Study Knowledge Label Laboratories Libraries Ligands Manuals Mediating Medicine Mentors Metals Methodology Methods Michigan Mission Modeling Monitor National Institute of Biomedical Imaging and Bioengineering Organometallic Chemistry Oxides Periodicity Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phase Population Analysis Positioning Attribute Positron-Emission Tomography Preparation Procedures Process Production Property Protocols documentation Quinine Radio Radioactive Radiochemistry Radioisotopes Radiolabeled Radiology Specialty Radiopharmaceuticals Reaction Research Research Design Research Proposals Role Salts Scanning Silver Silver Compounds Sodium Chloride Tracer Training Translating Universities Validation Vitamin B6 analog base 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 protocol development quinoline scaffold screening skills stable isotope translational study

项目摘要

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.

项目概要/摘要氟是许多商业分子的重要组成部分，包括（放射性）药物、农用化学品、功能材料。 Fluor-19（稳定同位素）通常被引入芳烃中药物以调节药理特性。多正电子发射断层扫描芳香族 (PET) 显像剂用氟 18（放射性同位素）标记，用于研究和监测疾病，如以及评估药物靶点参与和丰富临床试验。已经取得了长足的进步为这些应用开发芳香族氟 18 显像剂，尽管更稳健需要放射合成来支持和加速示踪剂发现并满足日益增长的需求来自医疗保健和制药行业的放射性药物。该项目的主要目的是通过发明放射合成方法克服与放射氟化相关的挑战支持芳香族 PET 显像剂的设计。具体来说，核心主张是放射性氟化有机物可以通过设计具有 C-H 能力的含银和铜物质来获得分子放射性氟化。铜是一种丰富且廉价的元素，之前已被证明可以（放射性）氟化芳香族 C-H 键，尽管范围有限。银与以下元素属于同一周期群：铜和初步数据表明它可以诱导 C-H 放射性氟化转变。为了实现这些目标，该提案分为三个目标：目标 1 是使用氟 18 标记的银化合物有机分子的放射性氟化。目标 2 是利用该方法进行氟的自动放射合成 18 个标记的生物活性分子目标 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、自动化氟 18 标记。最终，加强这一点本次资助中描述的成像方式预计将从根本上改变当前的放射合成范式并加速芳香族放射性氟化，提供新的、快速的氟 18 标记药物的获取用于PET。重要的是，PET 生物技术的发展不断被用于从根本上改善疾病的检测、治疗和预防，这与 NIBIB 的使命是一致的。这笔补助金建立在 Peter J. H. Scott 教授（放射科）之间持续进行的多学科合作的基础上和 Melanie S. Sanford 教授（化学系），专注于放射合成的发展密歇根大学的方法。这些实验室提供的设施和故障/人员专业知识提供卓越的研究环境，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，这符合他的长期职业目标。在特别是，该项目将为合并放射化学和有机金属化学提供新的机会，这将为候选人的职业发展提供帮助，使其成为化学教授，重点是 C-H PET 应用的放射性标记。