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

项目概要/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）通常被引入芳族化合物中。 药物以调节药理学性质。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 以及评估药物靶向作用和丰富临床试验。取得了相当大的进展 在用于这些应用的芳族氟-18成像剂的开发中， 需要放射性合成来支持和加速示踪剂发现，并满足对 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了与放射性同位素相关的挑战， 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 可以通过设计能够参与C-H的含银和铜物质来获得分子 无线电铜是一种丰富而廉价的元素，以前已经证明， （放射性）氟化芳族C-H键，尽管范围有限。银与铜属于同一周期族， 铜和初步的数据表明，它可以诱导C-H放射性转化。实现这些 目标，该提案分为三个目标：目标1是使用氟-18标记的银化合物用于 有机分子的放射性同位素。目的2是利用该方法自动放射合成氟- 目的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，增强这一点， 在这项资助中所描述的成像方式有望从根本上改变目前的放射合成范式 加快芳香族放射性的合成，提供新的和快速的氟-18标记药物 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，与NIBIB的使命一致。这笔赠款 建立在教授彼得J。Scott（放射科） Melanie S.桑福德（化学系），专注于放射性合成的发展 方法在密歇根大学。这些实验室提供的设施和故障/工作人员专业知识 提供一个优秀的研究环境，这将有利于候选人的进一步技能的收购 在美国机构获得学术职位所必需的，与他的长期职业目标一致。在 特别是，该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 用于PET应用的放射性标记。

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.