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

翻译后摘要：放射性示踪剂含有[18F]标记的富电子芳环是最受欢迎的- 在PET成像剂之后，但在历史上合成具有挑战性。最近的努力试图 改进用[18F]氟化物对（杂）芳烃的后期标记。特别是，过渡金属介导的 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， 铜介导的放射治疗（CMRF）已被证明是最通用的方法之一。上一 获得该奖项后，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 合成FDA批准的临床剂量。然而，尽管取得了许多成功， CMRF的广泛临床应用仍然存在以下问题：（a）许多重要的有机支架不相容 对于现有的CMRF方法，（B）自动化CMRF方法的产率通常是中等的，因此 不适合商业分销，以及（c）一次性卡匣技术不适用于CMRF， 自动化放射合成器，限制常规临床使用的放射性示踪剂生产。所有这些挑战将 在这个更新的建议中。总体目标是开发用于临床生产的稳健方法 多种PET放射性示踪剂。我们的中心假设是CMRF具有独特的定位，使我们能够实现 这个目标这项拟议中的研究将确定放射性氟化支架的新反应， 现有的CMRF（目标1），使用最先进的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 含有与现有CMRF（杂环如吡啶和 吗啉，药物分子，如GW 405833），以及优化的自动化方法和盒， 几十年来一直难以获得的放射性示踪剂（例如[18F]FDOPA）。建议的可行性 这些努力得到了广泛的初步结果的支持，这些结果为令人兴奋的新研究提供了基础。 方向我们的团队已经合作了7年，我们在过渡金属催化方面的专业知识（桑福德）， 放射化学（Scott）和机器学习（Doyle）使我们能够完成所提出的研究。 该项目的目标将通过各种创新来实现，包括：（1）制定方法， 从新的前体（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）开发用于进行放射化学的自动化盒 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。总体而言，这 该项目将提供多种新的方法来合成18F标记的放射性示踪剂，这些示踪剂是无法使用的。 现有的方法和重要放射性示踪剂的有效临床合成。所有这些可交付成果都将扩大 PET成像在疾病检测、治疗和预防中的应用。

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.