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

摘要：含有[18F]标记的富电子芳环的放射性示踪剂是目前最受关注的放射性示踪剂之一。 在PET显像剂之后，但历史上合成一直是具有挑战性的。最近的努力寻求 用[18F]氟化物改进(杂环)芳烃的后期标记特别是，过渡金属介导的 使用高摩尔活度[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。在上一次 获奖，我们报告了10个新的CMRF反应，验证了它们的良好制造规范(GMP)，并使用 以合成FDA批准的临床剂量。然而，尽管取得了许多成功，但几个关键挑战 CMRF的广泛临床应用：(A)许多重要的有机支架是不相容的 对于现有的CMRF过程，(B)自动CMRF方法的产量通常是中等的，因此 不适合商业发行，以及(C)CMRF上没有一次性盒式磁带技术 自动放射性合成器，限制常规临床使用的放射性示踪剂生产。所有这些挑战都将 在这份续签提案中得到了解决。总体目标是为临床生产开发可靠的方法。 不同的PET放射性示踪剂。我们的中心假设是，CMRF处于独特的地位，使我们能够实现 这个目标。拟议的研究将确定放射性氟化支架的新反应，这些反应与 现有的CMRF(AIM 1)，使用尖端的机器学习技术来提高自动化的CMRF收益率(AIM 2)，并开发使用CMRF可靠生产GMP临床放射性示踪剂的盒式磁带技术(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(如吡啶和吡啶等杂环)不兼容(或产率较低)的官能团 吗啉、GW405833等药物分子)，以及优化的自动化方法和盒式磁带 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 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(Sanford)方面的专业知识， 放射化学(Scott)和机器学习(Doyle)为我们完成拟议的研究提供了独特的定位。 项目目标将通过各种创新来实现，包括：(1)开发方法 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 机器学习在放射化学中的应用；(3)自动化盒带的研制 CMRF使用最新一代的放射合成器，专为即插即用生产而设计。总体而言，这 该项目将提供多种合成18F标记放射性示踪剂的新方法，这些方法无法使用 现有方法，并验证了重要放射性示踪剂的临床合成。所有这些交付成果都将扩大 PET成像在疾病的检测、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.