Copper-mediated Radiofluorination: from Proof-of-Concept to Clinical Impact

铜介导的放射性氟化：从概念验证到临床影响

• 批准号: 10209444
• 负责人: MELANIE S. SANFORD
• 金额: $ 37.73万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10209444
• 关键词: Address; Adoption; Automation; Award; Basic Science; Caring; Catalysis; Chemistry; Clinical; Clinical Trials; Copper; Data; Data Set; Development; Dose; Electrons; Emission-Computed Tomography; FDA approved; Fluorides; Fluorine; Generations; Goals; Grant; Growth; Hydrogen Bonding; Image Enhancement; Imaging Techniques; Label; Levodopa; Machine Learning; Manuals; Mediating; Mediator of activation protein; Medical; Methods; Modeling; Monitor; Multi-Institutional Clinical Trial; Nuclear; Paper; Patients; Pattern; Performance; Pharmaceutical Preparations; Pharmacy facility; Physiological Processes; Play; Positioning Attribute; Positron-Emission Tomography; Process; Production; Publishing; Radiochemistry; Radioisotopes; Radiolabeled; Reaction; Reporting; Reproducibility; Research; Side; Site; Techniques; Technology; Time; Transition Elements; Translating; Translations; Validation; aryl halide; base; clinical application; cost; design; disease diagnosis; disorder prevention; drug discovery; imaging agent; imaging detection; improved; in vivo monitoring; innovation; machine learning algorithm; method development; molecular imaging; morpholine; neural network; personalized medicine; preclinical imaging; predictive modeling; pyridine; radiotracer; random forest; scaffold; standard of care; success

Abstract: Radiotracers containing [18F]-labeled electron-rich aromatic rings are among the most highly sought- after PET imaging agents but have been historically challenging to synthesize. Recent efforts have sought to improve the late-stage labeling of (hetero)arenes with [18F]fluoride. In particular, transition metal-mediated reactions using high molar activity [18F]fluoride have changed the way radiochemists form C–18F bonds, and copper-mediated radiofluorination (CMRF) has proven one of the most versatile of approaches. In the previous award, we reported 10 new CMRF reactions, validated them for Good Manufacturing Practice (GMP), and used them to synthesize FDA-approved clinical doses. However, despite many successes, several key challenges remain for the widespread clinical application of CMRF: (a) many important organic scaffolds are incompatible with existing CMRF processes, (b) yields of automated CMRF methods are typically moderate and thus unsuitable for commercial distribution, and (c) disposable cassette technologies are not available for CMRF on automated radiosynthesizers, limiting radiotracer production for routine clinical use. All of these challenges will be addressed in this renewal proposal. The overall objective is to develop robust methods for clinical production of diverse PET radiotracers. Our central hypothesis is that CMRF is uniquely positioned to enable us to achieve this goal. The proposed research will identify new reactions to radiofluorinate scaffolds that are incompatible with existing CMRF (Aim 1), use cutting edge machine learning techniques to improve automated CMRF yields (Aim 2), and develop cassette technologies for reliable GMP production of clinical radiotracers using CMRF (Aim 3). The research is significant because it entails development of methods for radiolabeling bioactive molecules containing functionality that is incompatible (or low yielding) with existing CMRF (heterocycles like pyridine and morpholine, drug molecules like GW405833), as well as optimized automated methods and cassettes for radiotracers that have been challenging to access for decades (e.g. [18F]FDOPA). The viability of the proposed efforts is supported by extensive preliminary results that provide groundwork for the exciting new research directions. Our team has been collaborating for 7 years and our expertise in transition metal catalysis (Sanford), radiochemistry (Scott), and machine learning (Doyle) uniquely positions us to accomplish the proposed research. The project goals will be accomplished through a variety of innovations including: (1) developing methods for labeling challenging electron-rich (hetero)arenes from new precursors (C–H bonds, aryl halides), (2) the first application of machine learning to radiochemistry, and (3) development of automated cassettes for conducting CMRF using the newest generation of radiosynthesizers designed for plug-and-play production. Overall, this project will deliver multiple new methods for synthesizing 18F-labeled radiotracers that are inaccessible using existing methods, and validated clinical syntheses of important radiotracers. All of these deliverables will expand the utility of PET imaging for the detection, treatment, and prevention of disease.

摘要：含有[18F]标记的富电子芳环的放射性示踪剂是最受追捧的放射性示踪剂之一。 PET 显像剂之后，但历史上一直难以合成。 改善[18F]氟化物对（杂）芳烃的后期标记，特别是过渡金属介导的标记。 使用高摩尔活性[18F]氟化物的反应改变了放射化学家形成C-18F键的方式，并且 铜介导的放射性氟化（CMRF）已被证明是最通用的方法之一。 获奖后，我们报告了 10 个新的 CMRF 反应，验证了它们的良好生产规范 (GMP)，并使用 然而，尽管取得了许多成功，但仍面临一些关键挑战。 CMRF广泛的临床应用仍然存在以下问题：(a)许多重要的有机支架是不相容的 对于现有的 CMRF 工艺，(b) 自动化 CMRF 方法的产量通常适中，因此 不适合商业分销，并且 (c) 一次性盒技术不适用于 CMRF 自动化放射合成仪，限制了常规临床使用的放射性示踪剂的生产。 本更新提案中的总体目标是开发可靠的临床生产方法。 我们的中心假设是 CMRF 具有独特的优势，能够帮助我们实现这一目标。 拟议的研究将确定与放射性氟化物支架不相容的新反应。 现有的 CMRF（目标 1），使用尖端机器学习技术来提高自动化 CMRF 产量（目标 2)，并开发盒式技术，使用 CMRF 可靠地 GMP 生产临床放射性示踪剂（目标 3）。 这项研究意义重大，因为它需要开发放射性标记生物活性分子的方法 含有该功能的化合物与现有的 CMRF（杂环化合物，如吡啶和 吗啉、药物分子（如 GW405833），以及优化的自动化方法和盒 几十年来一直难以获取的放射性示踪剂（例如[18F]FDOPA）。 得到了广泛的初步结果的支持，这些努力为令人兴奋的新研究奠定了基础 我们的团队已经合作了 7 年，我们在过渡金属催化（桑福德）方面拥有专业知识， 放射化学（斯科特）和机器学习（多伊尔）使我们能够完成拟议的研究。 项目目标将通过各种创新来实现，包括：（1）开发方法 从新前体（C-H 键、芳基卤化物）标记具有挑战性的富电子（杂）芳烃，(2) 第一个 机器学习在放射化学中的应用，以及（3）开发用于进行的自动盒式磁带 CMRF 使用最新一代的无线电合成器，专为即插即用生产而设计。 该项目将提供多种新方法来合成 18F 标记的放射性示踪剂，而这些方法是无法使用 现有的方法，以及重要放射性示踪剂的经过验证的临床合成，所有这些交付成果都将得到扩展。 PET 成像在疾病检测、治疗和预防中的应用。