Diversifying Radiochemistry Toward Practical Approaches for the Synthesis and Application of Imaging Agents

正电子发射断层扫描（PET）是用于早期疾病诊断和治疗的高精度成像工具 功效监测。对新显像剂的持续需求以及实用、稳健、选择性的缺乏 其合成方法需要扩展现有的放射化学技术。在具体目标中，我们 提出了一种新的假肢组方法以实现 18F 合并。氟18是优选的，因为它具有良好的 正电子发射特性和更长的半衰期（t1/2 = 110 分钟），因此可以远程生产显像剂 并分发给医院。通过后期官能团对复杂分子进行传统的放射性氟化 相互转化受到每种前体合成困难的限制。替代方法依赖于 直接 C-H 激活方法还处于初级阶段。它们表现出低放射化学产率 (RCY) 氟化位点的固有底物控制，这可能限制靶标结合。低选择性， 这种方法的共同点可能会导致不可分离的异构体混合物，从而阻止这些药物的临床使用 PET 成像探头符合 FDA 法规。假肢组方法尽管需要一个额外的步骤， 提供完美的氟位点选择性。我们提出的修复方法具有强大的氟化功能，可轻松实现 可接近的末端烯烃，然后快速形成 C-C 键，以合成多种放射性氟化物 化合物。如果成功，它将允许前所未有地使用芳香族、杂芳香族和芳香族化合物。 脂肪族基团具有 PET 成像所需的功能。在具体目标 II 中，我们提出了应用 可见光诱导钯化学快速杂化 11C-甲基自由基加成生成 放射性甲基化显像剂。碳 11 的半衰期比氟 18 短得多（t1/2 = 20 分钟），因此 放射性示踪剂的合成极具挑战性。目前 11C 掺入的方法依赖于甲基化， 杂原子的亲核取代是最常见的策略。偶联反应少得多 已经报道了化学计量方法的发展。预计我们的混合激进方法 可以改进 11C 标记 PET 显像剂的快速甲基化方法。在具体目标 III 中，我们将 应用正在开发的拟议方法来合成靶向 HIF2α 的药物库，并 tau蛋白。 PET 成像最重要的应用涉及早期诊断和治疗进展 监测癌症和神经退行性疾病。基于已发表的抑制剂的结构特征 和放射性配体，我们选择了我们提出的方法的两个潜在应用：HIF2α，一种转录因子 选择性地见于某些恶性肿瘤，其表达为阴性预后；和 tau 蛋白，一个标志 神经退行性疾病，例如阿尔茨海默病。 “冷”化学反应将在 德克萨斯大学达拉斯分校和该大学高级成像研究中心的放射化学 德克萨斯西南医学中心，作为 PI 博士前培训计划的一部分，其中包括全面 时间研究辅以指导和专业发展。

Positron Emission Tomography (PET) is a high precision imaging tool for early disease diagnosis and treatment efficacy monitoring. A continuous demand for new imaging agents and the absence of practical, robust, selective methods for their synthesis calls for expanding the existing radiochemistry technologies. In Specific Aim I we propose a new prosthetic group approach toward 18F incorporation. Fluorine-18 is preferred for its favorable positron emission properties and longer half-life (t1/2 = 110 min), so imaging agents can be produced remotely and distributed to hospitals. A traditional radiofluorination of complex molecules by late-stage functional group interconversion is limited by challenging synthesis of each precursor. The alternative approaches relying on direct C–H activation methodologies are at their nascent stages. They exhibit low radiochemichal yields (RCY) and innate substrate control of the fluorination sites, which can be restrictive to target binding. Low selectivity, common to this approach, might result in inseparable isomer mixtures, thus preventing the clinical use of these PET imaging probes due to FDA regulations. The prosthetic group approach, despite requiring one extra step, offers perfect fluorine site-selectivity. Our proposed prosthetic method features robust fluorination at easily accessible terminal olefins followed by rapid C–C bond formation toward the synthesis of diverse radiofluorinated compounds. If successful, it would allow unprecedented access to the use of aromatic, heteroaromatic, and aliphatic groups bearing desirable functionalities for PET imaging. In Specific Aim II we propose the application of visible light-induced palladium chemistry toward rapid hybrid 11C-methyl radical addition to produce radiomethylated imaging agents. Carbon-11 has a much shorter half-life than fluorine-18 (t1/2 = 20 min), so radiotracer synthesis is extremely challenging. The current methods for 11C-incorporation rely on methylation, with nucleophilic substitution of heteroatoms as the most common strategy. Coupling reactions are much less developed though stoichiometric approaches have been reported. It is expected that our hybrid radical approach could improve methods for rapid methylation toward 11C-labeled PET imaging agents. In Specific Aim III we will apply the proposed methods under development toward the synthesis of a library of agents to target HIF2α and tau prions. The most important applications of PET imaging concern early diagnosis and treatment progression monitoring of cancer and neurodegenerative diseases. Based on the structural features of published inhibitors and radioligands, we selected two potential applications of our proposed methods: HIF2α, a transcription factor selectively found in certain malignancies, whose expression is a negative prognosis; and tau protein, a hallmark of neurodegenerative diseases, such as Alzheimer’s Disease. The “cold” chemistry will be carried out at The University of Texas at Dallas and the radiochemistry at the Advanced Imaging Research Center at The University of Texas Southwestern Medical Center, as part of the pre-doctoral training plan of the PI, which includes full- time research complemented by mentorship and professional development.