Novel Catalytic Methods for Efficient Radiolabeling of Un-activated Arene Compounds

摘要 正电子发射断层扫描(PET)是一项功能强大、发展迅速的技术，在 医学成像，以及药物发现和开发。尽管PET成像有着不同寻常的前景， 由于缺乏有效和简单的标记方法，PET试剂的可用性在许多情况下都受到限制 修饰具有生物活性的小分子/药物。基于描述的高度创新的光氧化还原系统 由Nicewicz小组(Science，2015,349,1326-1330)进行的这项研究将解决对新型PET的需求 通过建立广泛适用的晚期放射性氟化和放射性氰化方法来制备显像剂 芳香底物。建议的方法可以通过以下方式对成像领域产生革命性影响 为以前难以或不可能合成的新型PET试剂提供了途径。确实有 这个应用程序有三个目标。目的1寻求开发具有不同电子密度的光触媒文库， 放射性标记未活化芳环的空间构型和光物理特性。AIM 2将开发C-H [18F]芳烃的有机光催化氟化和C-H[11C]氰化。目标3将建立小说 苯酚衍生物的亲核芳香族取代反应生成[18F]芳烃和[11C]-CN-芳烃。 这一应用的一个关键优势是所建议方法的大量初步数据。我们已经做好了 18F-直接芳烃C-H氟化的第一个突破(《科学》，2019，正在出版中)，不仅允许 不仅可以将药物直接转化为PET试剂，而且还可以实现快速的配基筛选，如工作示例所示。 对于C-O到C-F的直接转换，我们也证明了该方法是有效的，具有良好的放射性标记产率。 “冷”氰化反应已经建立，并准备进行放射性标记测试。考虑到所有这些因素 总之，拟议的研究将导致一种全新的方法，将[18F]F和[11C]CN并入 使用晚期放射性标记的芳香族化合物。温和的条件加上容易获得所需的 前体将允许前所未有地获得用于神经学、肿瘤学、 以及其他各种研究领域，将在这些领域产生很高的影响。

Abstract Positron emission tomography (PET) is a powerful and rapidly developing technology that plays key roles in medical imaging, as well as drug discovery and development. Despite the exceptional promise of PET imaging, the availability of PET agents is limited in many situations due to the lack of efficient and simple labeling methods to modify biologically active small molecules/drugs. Based on the highly innovative photoredox system described by the Nicewicz group (Science, 2015, 349, 1326-1330), this research will address the need for novel PET imaging agents by establishing broadly-useful methodologies for late-stage radiofluorination and radiocyanation of aromatic substrates. The proposed approaches could have transformative impacts on the imaging field by providing access to novel PET agents that are previously challenging or impossible to synthesize. There are three aims in this application. Aim 1 seeks to develop a photocatalyst library with different electron density, sterics and photophysical characteristics for radiolabeling unactivated aromatic rings. Aim 2 will develop C–H [18F]fluorination and C–H [11C]cyanation of arenes via organic photoredox Catalysis. Aim 3 will establish novel nucleophilic aromatic substitution reactions of phenol derivatives to afford [18F]aromatics and [11C]–CN-aromatics. A key strength of this application is the extensive preliminary data for the proposed approaches. We have make the first breakthrough on direct arene C–H fluorination with 18F– (Science, 2019, in press) that not only allows direct conversion of drugs to PET agents, but also enables fast ligand screening as shown in working examples. For C–O to C–F direct conversion, we also demonstrated the approach is valid with excellent radiolabeling yields. The “cold” cyanation reactions have been established and ready for radiolabeling testing. Taking all these factors together, the proposed research will lead to an entirely new method for incorporation of [18F]F and [11C]CN into aromatic compounds using late stage radiolabeling. The mild conditions coupled with easy access to the required precursors will allow for the unprecedented access to novel aromatic PET tracers of use in neurology, oncology, and various other research area, which will generate high impact in those fields.