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转化为 候选正电子发射断层扫描(PET)试剂通过放射性氟化，容易获得，和 廉价的LED光源。宠物是一项功能强大、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。尽管有不同寻常的承诺，但小说的可用性 由于缺乏有效和简单的标记方法来修饰具有生物活性的小分子，因此宠物制剂受到限制 分子/药物。许多小分子药物和治疗药物含有芳香族或杂芳族 在其框架内的系统；因此，将无线电标记引入这一共同的 有机亚基轻松高效。 不幸的是，目前对失活芳烃化合物进行放射性氟化的方法只取得了有限的成功，而且 通常需要复杂的合成来获得所需的前体和/或特殊的无氧处理 技巧。然而，随着Nicewicz和Li开发的光氧化还原系统取得了进展 在北卡罗来纳大学教堂山分校的研究小组；他们的工作描述了18F-C-H氟化反应。 这使得药物可以直接转化为PET试剂。他们还确定了亲核芳香族化合物 取代(SNAR)和卤素交换反应可以精确控制放射性氟化的位置 进行C-OR2或C-X(X=F、Cl、Br、I、NO2)键的放射性氟化时的芳香族底物。而这些 方法提供简单、有效的晚期放射氟化，两种方法都需要昂贵的激光。 源，预计设置可能很难实现自动化。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)可以为未满足的需求提供答案 多种PET试剂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确定所设想的放射性氟化装置的可行性 使这一范式转变的技术易于应用于该领域。这一阶段的具体目标是 项目内容为：1.研制了一种基于流动反应和微流控技术的LED光源样机 源，目标是在不影响放射性标记产量的情况下大大降低光反应堆的成本。 支持合成[18F]F-DOPA衍生物的初始模块将与该设备共同开发，如 这种成熟的光氧化还原放射性标记反应可以在该设备上进行演示和优化， 和2：通过对一类现有小分子的成员进行氟化来展示这一概念的能力 制药公司。根据目标1中确定的初始设计，确定的三种合成方法将 将在AIM 1内置的设备中开发和测试。LED放射流体学假设微流控设备将 大大增加了暴露在光源下的表面积，与传统的 设置好了。

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.