Fluoride-Mediated Desilylative Radiosynthesis of 11C-Labeled PET Tracers

氟化物介导的 11C 标记 PET 示踪剂的脱甲硅烷基放射合成

• 批准号: 10610450
• 负责人: Wenchao Qu
• 金额: $ 35.58万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10610450
• 关键词: Acetic Acids; Address; Affinity; Aldehydes; Amides; Anions; Atmosphere; Basic Science; Biochemical; Biological; Carbon; Carbon Dioxide; Carboxylic Acids; Cardiovascular system; Catalysis; Chemicals; Chemistry; Clinical; Clinical Research; Cyclotrons; Development; Disease; Electrons; Esters; Event; Fatty Acids; Fluorides; Gases; Goals; Half-Life; Imaging Device; Imaging Techniques; In Situ; Intervention; Investigation; Label; Lead; Longitudinal Studies; Low Dose Radiation; Mediating; Metabolism; Metals; Methodology; Methods; Methylation; Modality; Molecular; Neurologic; Nitrogen; Nuclear; Oncology; Organism; Oxygen; Palmitic Acids; Positioning Attribute; Positron; Positron-Emission Tomography; Production; Property; Pyruvic Acid; Radio; Radiochemistry; Radioisotopes; Radiolabeled; Reaction; Reagent; Reporting; Research; Research Personnel; Scanning; Skeleton; Solvents; Source; Structure; Succinic Acids; Sulfonamides; Sulfur; Temperature; Thermodynamics; Tracer; Translating; Vorozole; biological systems; carboxylate; carboxylation; chemical property; clinical diagnostics; drug-like compound; enzyme substrate; functional group; image translation; in vivo; interest; molecular imaging; novel; novel strategies; pharmacologic; radiochemical; radiotracer; receptor binding; screening

PROJECT SUMMARY Positron emission tomography (PET) is a highly sensitive molecular imaging technique used for studying biological systems in vivo, as well as for clinical diagnostic purposes. The ubiquitous presence of carbon in most organic molecules makes carbon-11 an attractive and important positron-emitting radionuclide for labeling molecules of biological interest. Because 11C has the same chemical properties as 12C, 11C is especially useful for rapid exploration of molecules with well-characterized biological and pharmacological properties (i.e., metabolism, receptor binding affinity, enzyme substrate affinity, etc.). In addition, the short half- life of 11C (20.4 min) facilitates the possibility of multiple studies on the same subject in a single day due to the low radiation dose and absence of overlapping activity between scans. This opens up the possibility for longitudinal studies and studies involving an intervention, making it particularly desirable for basic and clinical research investigations. The lack of methods to introduce and incorperate11C into organic molecules conveniently and quickly limits the utility of this radioisotope. So far, the main criteria for successful synthesis of 11C-lableled PET tracers is a rapid, robust and practical radiolabeling method that yields the desired tracer with high radiochemical purity, chemical purity, and/or high molar activity. This is especially a challenge when [11C]CO2 is used as radiosynthon for synthesis of desired PET tracers. In this proposal, we will develop methods to address this issue. Our three Specific Aims are: 1). develop a fluoride-mediated desilylation (FMDS) 11C-labeling methodology to directly incorporate [11C]CO2 into skeleton of molecules with diversified structures. It is expected that this novel approach will provide facile and rapid access to 11C-labeled compounds with carbon-11 attached at various hybridized carbons (sp, sp 2 and sp3) with broad functional group tolerance; 2). Further extend FMDS 11C-labeling methodology to other accessible 11C-electrophiles (such as [11C]CH3I/[11C]CH3OTf). Our goal is to develop a new 11C-methylation method, which can serve as a complementary approach for synthesis of various 11C-labeled PET tracers; 3). Utilize FMDS 11C-labeling to solve some long-standing problems in radiotracer chemistry research by developing facile and practical labeling methods for radiotracers of high clinical interest where regular production is very difficult using currently reported methods, such as [11C]pyruvic acid, [11C]succinic acid, [11C]PHNO, [11C]vorozole. This newly developed FMDS 11C-labeling methodology may lead a brand new direction in radiotracer chemistry and open multiple avenues for developing novel and practical radiolabeling methodologies.

项目概要 正电子发射断层扫描（PET）是一种高灵敏度的分子成像技术，用于研究 体内生物系统以及临床诊断目的。碳的存在无处不在 大多数有机分子使碳 11 成为一种有吸引力且重要的正电子发射放射性核素 标记具有生物学意义的分子。由于 11C 的化学性质与 12C 相同，因此 11C 特别适用于快速探索具有良好生物学和药理学特征的分子 性质（即代谢、受体结合亲和力、酶底物亲和力等）。此外，短半 11C 的寿命（20.4 分钟）促进了一天内对同一主题进行多项研究的可能性，因为 辐射剂量低且扫描之间不存在重叠活动。这开辟了可能性 纵向研究和涉及干预的研究，使其特别适合基础和临床 研究调查。缺乏将11C引入并掺入有机分子的方法 方便快捷地限制了这种放射性同位素的用途。到目前为止，成功合成的主要标准 11C 标记 PET 示踪剂是一种快速、稳健且实用的放射性标记方法，可产生所需的示踪剂 具有高放射化学纯度、化学纯度和/或高摩尔活性。这尤其是一个挑战，当 [11C]CO2 用作放射合成剂来合成所需的 PET 示踪剂。在本提案中，我们将开发 解决这个问题的方法。我们的三个具体目标是：1)。开发氟化物介导的脱甲硅烷基化 (FMDS) 11C标记方法可直接将[11C]CO2整合到多样化分子骨架中 结构。预计这种新颖的方法将提供方便、快速地获取 11C 标记的 碳 11 连接在各种杂化碳（sp、sp 2 和 sp3）上的化合物，具有广泛的功能 群体宽容； 2）。将 FMDS 11C 标记方法进一步扩展到其他可接近的 11C 亲电子试剂（例如 为 [11C]CH3I/[11C]CH3OTf)。我们的目标是开发一种新的11C-甲基化方法，该方法可以作为 用于合成各种 11C 标记 PET 示踪剂的补充方法； 3）。利用 FMDS 11C 标签 通过开发简便实用的方法解决放射性示踪剂化学研究中长期存在的一些问题 临床高度关注的放射性示踪剂的标记方法，但常规生产很难使用 目前报道的方法有[11C]丙酮酸、[11C]琥珀酸、[11C]PHNO、[11C]伏罗唑等。这个新 开发的FMDS 11C标记方法可能会引领放射性示踪剂化学的全新方向并开放 开发新颖实用的放射性标记方法的多种途径。