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

放射化学多样化，迈向显像剂合成和应用的实用方法

• 批准号: 10216180
• 负责人: Mónica Rivas
• 金额: $ 4.6万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216180
• 关键词: Alkenes; Alzheimer' s Disease; Binding; Carbon; Chemistry; Clinical; Complement; Complex; Coupling; Development; Early Diagnosis; Early treatment; Electron Transport Complex III; Exhibits; Fluorine; Half-Life; Hospitals; Hybrids; Image; Imaging Device; Isomerism; Knowledge; Label; Libraries; Malignant Neoplasms; Medical center; Mentorship; Methodology; Methods; Methylation; Modeling; Monitor; Neurodegenerative Disorders; Palladium; Positron; Positron-Emission Tomography; Prions; Prognosis; Property; Prosthesis; Protocols documentation; Publishing; Radiochemistry; Radiopharmaceuticals; Reaction; Regulation; Reporting; Research; Site; Structure; Synthesis Chemistry; Tauopathies; Technology; Texas; Time; Tracer; Training; Treatment Efficacy; Universities; Visible Radiation; Work; analog; aryl halide; base; clinical application; design; disease diagnosis; functional group; imaging agent; imaging probe; improved; inhibitor/antagonist; methyl radical; novel; nucleophilic substitution; pre-doctoral; prevent; radiochemical; radioligand; radiotracer; rapid technique; tau Proteins; tool; transcription factor

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.

正电子发射断层扫描（PET）是一种用于早期疾病诊断和治疗的高精度成像工具 疗效监测对新的显像剂的持续需求和缺乏实用的、稳健的、选择性的显像剂， 它们的合成方法要求扩展现有的放射化学技术。在具体目标I中，我们 提出了一种新的辅基方法对18F掺入。氟-18由于其有利的特性而优选。 正电子发射特性和更长的半衰期（t1/2 = 110 min），因此可以远程生产成像剂 并分发到医院。一种传统的复杂分子的后期功能团放射性识别方法 相互转化受到每种前体的挑战性合成的限制。替代方法依赖于 直接的C-H活化方法正处于其新生阶段。它们表现出低放射化学产额（RCY） 以及对靶位点的先天底物控制，其可限制靶结合。低选择性， 这种方法的共同点是，可能会产生不可分离的异构体混合物，从而阻止这些异构体的临床应用。 PET成像探头符合FDA规定。假肢组的方法，尽管需要一个额外的步骤， 提供了完美的氟位点选择性。我们提出的修复方法具有鲁棒性， 可接近的末端烯烃，然后快速C-C键形成，以合成各种放射性氟化的 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 具有PET成像所需官能团的脂族基团。在具体目标II中，我们提出了应用 可见光诱导的钯化学向快速混合11 C-甲基自由基加成， 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。目前用于11 C-掺入的方法依赖于甲基化， 其中杂原子的亲核取代是最常见的策略。偶联反应少得多 尽管已经报道了化学计量方法。预计我们的混合激进方法 可以改进快速甲基化11 C标记PET显像剂的方法。在第三阶段，我们将 将正在开发的拟议方法应用于靶向HIF 2 α的试剂库的合成， tau朊病毒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：HIF 2 α，一种转录因子， 选择性地发现于某些恶性肿瘤，其表达是阴性预后;和tau蛋白，标志物 神经退行性疾病，如阿尔茨海默氏症“冷”化学将在 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 德州西南医学中心，作为PI的博士前培训计划的一部分，其中包括完整的- 时间研究辅之以导师和专业发展。

项目成果

One-Pot Formal Carboradiofluorination of Alkenes: A Toolkit for Positron Emission Tomography Imaging Probe Development.

• DOI: 10.1021/jacs.3c04548
• 发表时间: 2023-08
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Mónica Rivas;Sashi Debnath;S. Giri;Yusuf M Noffel;Xiankai Sun;V. Gevorgyan