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

摘要 正电子发射断层扫描（PET）是一种功能强大且发展迅速的技术，在以下方面发挥着关键作用： 医学成像以及药物发现和开发。尽管PET成像有着非凡的前景， 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受到限制 修饰生物活性小分子/药物。基于高度创新的光氧化还原系统描述 由Nicewicz小组（Science，2015，349，1326-1330），该研究将解决对新型PET的需求。 通过建立用于后期放射性显影和放射性氰化的广泛有用的方法 芳香基质的。所提出的方法可以通过以下方式对成像领域产生变革性影响： 提供了获得先前具有挑战性或不可能合成的新型PET试剂的途径。有 本申请的三个目的。目标1寻求开发具有不同电子密度的光催化剂库， 用于放射性标记未活化芳环的空间和物理特性。Aim 2将开发C-H 通过有机光氧化还原催化的芳烃的[18F]取代和C-H [11 C]氰化。目标3将建立新的 苯酚衍生物的亲核芳族取代反应，得到[18 F]芳族化合物和[11 C]-CN-芳族化合物。 该应用程序的一个关键优势是所提出的方法的广泛的初步数据。我们已经取得了 直接芳烃C-H取代18F-的第一个突破（Science，2019，出版中），不仅允许 如工作实施例中所示，本发明不仅能够将药物直接转化为PET剂，而且还能够进行快速配体筛选。 对于C-O到C-F的直接转化，我们还证明了该方法是有效的，具有优异的放射性标记产率。 “冷”氰化反应已经建立，并准备进行放射性标记试验。把所有这些因素 总之，拟议的研究将导致一个全新的方法，将[18 F]F和[11 C]CN纳入 使用后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， 和其他各种研究领域，这将在这些领域产生很大的影响。

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.