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：
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
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/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

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.

项目摘要/摘要氟是许多商业分子的重要组成部分，包括（无线电）药物，农业化学和功能材料。氟-19（稳定的同位素）常规引入芳香族药物以调节药理特性。许多正电子发射断层扫描芳香（PET）成像剂用氟-18（放射性同位素）标记用于研究和监测疾病，如以及评估药物目标参与并丰富临床试验。取得了很大进展在为这些应用开发芳族氟-18成像剂时，尽管更强大需要射线合成以支持和加快示踪剂发现并满足对不断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性合成方法来克服与辐射氟化有关的挑战支持芳香宠物成像剂的设计。具体而言，中心主张是射射荧光有机可以通过在C-H中设计富含银和铜的物种来访问分子放射性氟化。铜是一个丰富且便宜的元素，以前已显示为（无线电）氟芳族芳香族C-H键，尽管范围有限。银居住在同一周期组中铜和初步数据表明它可以诱导C-H射射荧光转换。实现这些目标，该提案分为三个目标：目标1是使用氟-18标记的银化合物进行有机分子的放射性氟。 AIM 2是利用此方法进行氟的自动辐射合成 18标记的生物活性分子目标3是开发新的铜介导的C-H功能化方法对于芳族生物活性分子的直接，自动氟-18标记。最终，增强了这一点如本赠款所述的成像方式有望从根本上改变当前的放射性合成范式并加速芳香族性氟化，可为氟-18标记的药物提供新的快速访问用于宠物。重要的是，宠物生物技术的发展不断用于根本上改善疾病的检测，治疗和预防，与尼比布的任务一致。这笔赠款建立在彼得·J·斯科特（Peter J. H. Scott）教授（放射学系）之间正在进行的多学科合作的基础上和梅兰妮·桑福德教授（化学系），重点是开发放射性合成密歇根大学的方法。这些实验室提供的设施和错误/员工专业知识提供杰出的研究环境，以促进候选人获得进一步的技能与他的长期职业目标一致的美国机构获得学术职位所必需的。在特别是，该项目将为合并放射化学和有机金属化学的新机会，这将为候选人的职业发展提供朝着化学教授职位，重点关注C-H 放射性标记用于宠物应用。