Development of LED Photoredox Radiolabeling Device

摘要 LED Radiofluidics正在开发一种设备，可以直接或轻松地将小分子药物 通过放射性核素显像获得正电子发射断层扫描（PET）试剂的候选者， 廉价的LED光源。PET是一种功能强大、发展迅速的技术，在医疗领域发挥着关键作用。 成像以及药物发现和开发。尽管有特殊的承诺，小说的可用性 由于缺乏有效和简单的标记方法来修饰生物活性小分子，PET试剂是有限的。 分子/药物。许多小分子药物和治疗剂含有芳族或杂芳族化合物， 因此，非常希望将放射性标记引入到这种常见的 有机亚基。 不幸的是，目前放射性氟化失活芳烃化合物的方法仅具有有限的成功， 通常需要复杂的合成以获得所需的前体和/或特殊的无氧处理 技术.然而，随着Nicewicz和Li开发的光氧化还原系统， 在查佩尔山的北卡罗来纳州大学的研究小组;他们的工作描述了芳烃C-H键与18 F- 它允许药物直接转化为PET试剂。他们还确定亲核芳香族化合物 取代（SNAr）和卤素交换反应可以精确地控制放射性同位素在 当进行C-OR 2或C-X（X = F、Cl、Br、I、NO 2）键的放射性解离时，虽然这些 方法提供了简单、有效的后期放射治疗，这两种方法都需要昂贵的激光 源代码，并且预计设置可能难以自动化。然而，LED Radiofluidics的创新 和负担得起的设备，使用廉价的光源（约200美元）可以提供一个未满足的需求， 通过我们基于光氧化还原的放射性氟化PET试剂的开发， 本申请的目的是作为第一步建立设想的无线电设备的可行性 使这种范式转换技术随时可用于该领域。第一阶段的具体目标 项目包括：1：开发基于流动反应和微流体的原型装置，使用LED作为光源 源，其目标是大大降低光反应器的成本而不损害放射性标记产率。 支持合成[18 F]F-DOPA衍生物的初始模块将与该设备共同开发，例如 这种公认的光氧化还原放射性标记反应可以在装置上得到证明和优化， 和2：通过氟化一类现有小分子的成员来证明该概念的能力 大药厂根据目标1中建立的初始设计，确定的三种合成方法将 在Aim 1中内置的设备中进行开发和测试。LED Radiofluidics假设微流体设备将 大大增加了暴露于光源的表面积，从而导致与传统技术相比产量增加。 安排

Abstract LED Radiofluidics is developing an apparatus that allows direct or easy conversion of small molecule drug candidates to positron emission tomography (PET) agents via radiofluorination with a readily accessible, and inexpensive LED light source. PET is a powerful, rapidly developing technology that plays key roles in medical imaging, as well as drug discovery and development. Despite the exceptional promise, the availability of novel PET agents is limited due to the lack of efficient and simple labeling methods to modify biologically active small molecules/drugs. Many small molecule pharmaceuticals and therapeutics contain aromatic or heteroaromatic systems within their framework; thus, it would be highly desirable for radiolabels to be introduced to this common organic subunit easily and efficiently. Unfortunately, current methods to radiofluorinate inactivated arene compounds have only limited success, and often requires complicated synthesis to access the desired precursors and/or special O2-free handling techniques. Progress has been made however, with photoredox systems developed by the Nicewicz and Li groups at the University of North Carolina at Chapel Hill; their work describes arene C–H fluorination with 18F – that allows direct conversion of drugs to PET agents. They also have determined that the nucleophilic aromatic substitution (SNAr) and halogen exchange reactions can precisely control the radiofluorination position on aromatic substrates when conducting radiofluorination of C-OR2 or C-X (X = F, Cl, Br, I, NO2) bonds. While these approaches offer simple, efficient late stage radiofluorination, both methods require an expensive laser light source, and it is anticipated that the setup could be difficult to automate. However, LED Radiofluidics’ innovative and affordable device, using an inexpensive light source (~$200) can offer an answer for the unmet need for diverse PET agents via our photoredox-based development of radiofluorinated PET agents. The goal of this application is to establish feasibility of the envisioned radiofluorination device as a first step toward making this paradigm shifting technology readily available to the field. The specific aims of this Phase I project are: 1: To develop a prototype device based on flow reaction and microfluidics using an LED as the light source, with the goal of greatly reducing the cost of the light reactor without compromising radiolabeling yields. An initial module supporting synthesis of an [18F]F-DOPA derivative will be co-developed with the device, such that this well-established photoredox radiolabeling reaction can be demonstrated and optimized on the device, and 2: To demonstrate the ability of the concept by fluorinating members of a class of existing small molecule pharmaceuticals. Informed by the initial design established in Aim 1, the three synthetic methods identified will be developed and tested in the device built in Aim 1. LED Radiofluidics hypothesize the microfluidic device will greatly increase the surface area exposed to the light source, leading to increased yields compared to traditional set-ups.