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

正电子发射断层扫描(PET)是一种用于疾病早期诊断和治疗的高精度成像工具 药效监测。对新显像剂的持续需求，缺乏实用、可靠、选择性强的显像剂 它们的合成方法需要扩展现有的放射化学技术。在特定的目标中，我我们 提出了一种新的18F掺入假体群方法。氟-18因其良好的性能而备受青睐 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。通过晚期官能团对复杂分子进行传统的放射性氟化 相互转化受到每一种前体合成困难的限制。另一种方法依赖于 直接C-H激活方法正处于萌芽阶段。它们表现出较低的放化产额(RCY) 以及对氟化位点的天然底物控制，这可能对靶标结合具有限制性。选择性低， 这种方法常见的，可能会导致不可分离的异构体混合物，从而阻止了这些 由于FDA的规定，PET成像探头。假肢组的方法，尽管需要额外的一个步骤， 提供完美的氟位置选择性。我们建议的假体方法具有很强的氟化作用 易接近的末端烯烃随后快速形成C-C键以合成各种放射性氟化物 化合物。如果成功，它将允许史无前例地使用芳香族、杂芳族和 具有理想的PET成像功能的脂肪族基团。在具体的目标二中，我们提出了应用 可见光诱导钯化学向快速杂化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)，所以 放射性示踪剂的合成是极具挑战性的。目前的11C-掺入方法依赖于甲基化， 以杂原子的亲核取代为最常见的策略。偶联反应要少得多 虽然已经报道了化学计量学方法的发展。预计我们的混合激进方法 可以改进11C标记的PET显像剂的快速甲基化方法。在第三个具体目标中，我们将 将正在开发的建议方法应用于合成靶向hif2α和 蛋白酪蛋白。PET成像最重要的应用是早期诊断和治疗进展 监测癌症和神经退行性疾病。根据已发表的缓蚀剂的结构特征 和放射性配基，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 选择性地在某些恶性肿瘤中发现，其表达是阴性预后；以及tau蛋白，一个标志 神经退行性疾病，如阿尔茨海默病。这种“冷”的化学反应将在 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 作为PI博士前培训计划的一部分，该计划包括 时间研究，辅以导师和专业发展。

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.