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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要正电子发射断层扫描（PET）是一种高度敏感的分子成像技术，用于研究体内生物系统以及用于临床诊断目的。无处不在的碳大多数有机分子使碳11使其成为吸引人且重要的发射正电子放射性核素的标记生物学兴趣的分子。因为11c具有与12C相同的化学特性，所以11c为11c 特别有用，可快速探索具有良好特征生物学和药理的分子特性（即代谢，受体结合亲和力，酶底物亲和力等）。另外，短的半 11c（20.4分钟）的寿命有助于在一天之内对同一主题进行多次研究的可能性扫描之间的低辐射剂量和不存在重叠活性。这打开了可能性涉及干预的纵向研究和研究，使其对于基本和临床特别理想研究调查。缺乏将有机分子引入和不渗透11c的方法方便，迅速地限制了该放射性同位素的实用性。到目前为止，成功合成的主要标准 11c层的宠物示踪剂是一种快速，健壮和实用的放射性标记方法，可产生所需的示踪剂具有较高的放射化学纯度，化学纯度和/或高摩尔活性。这尤其是一个挑战 [11C] CO2用作合成所需宠物示踪剂的放射性。在此提案中，我们将发展解决此问题的方法。我们的三个具体目标是：1）。开发氟化物介导的脱氨基化（FMDS）11C标记的方法，将[11C] CO2直接掺入具有多样化的分子骨骼中结构。预计这种新颖的方法将为11C标记提供便捷而快速的访问具有较宽功能性的各种杂化碳（SP，SP 2和SP3）附着的碳11化合物（SP，SP 2和SP3）群体容忍； 2）。进一步将FMDS 11C标记方法扩展到其他可访问的11C电子噬菌体（此类 AS [11C] CH3I/[11C] CH3OTF）。我们的目标是开发一种新的11C-甲基化方法，可以用作合成各种11C标记的宠物示踪剂的互补方法； 3）。利用FMDS 11C标记为通过开发便捷和实用来解决放射性训练化学研究中的一些长期问题高临床兴趣的放射性示例的标签方法，而常规产生非常困难目前报道的方法，例如[11C]丙酮酸，[11C]琥珀酸，[11C] PHNO，[11C]伏唑啉。这个新开发的FMDS 11C标签方法可能会在放射性固定化学方面领导全新的方向用于开发新颖和实用的放射标记方法的多种途径。