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

项目摘要 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 生物体内系统，以及用于临床诊断目的。碳元素的普遍存在 大多数有机分子使碳-11成为有吸引力的和重要的正电子发射放射性核素， 标记生物学感兴趣的分子。因为11 C具有与12 C相同的化学性质，所以11 C是 特别适用于快速探索具有良好表征的生物学和药理学性质的分子， 特性（即，代谢、受体结合亲和力、酶底物亲和力等）。此外，短半- 11 C（20.4分钟）的寿命有助于在一天内对同一受试者进行多项研究， 低辐射剂量和扫描之间不存在重叠活动。这就为 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11 C引入和掺入有机分子的方法 方便和快速地限制了这种放射性同位素的应用。到目前为止，成功合成的主要标准 11 C标记PET示踪剂是一种快速、稳健和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， [11 C]CO2用作合成所需PET示踪剂的放射性合成子。在本提案中，我们将开发 方法来解决这个问题。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）11 C标记方法，将[11 C]CO2直接结合到具有多种 结构.预计这种新的方法将提供方便和快速的11 C标记的 碳-11连接在各种杂化碳（sp、sp 2和sp 3）上的化合物， 群体耐受性; 2）.进一步将FMDS 11 C-标记方法扩展到其他可接近的11 C-亲电体（例如 作为[11 C] CH 3 I/[11 C] CH 3 OTf）。我们的目标是开发一种新的11 C-甲基化方法， 用于合成各种11 C标记的PET示踪剂的互补方法; 3）.利用FMDS 11 C标签， 通过研制简便实用的放射性示踪剂，解决了放射性示踪剂化学研究中一些长期存在的问题， 用于具有高度临床意义的放射性示踪剂的标记方法， 目前报道的方法，如[11 C]葡糖酸、[11 C]琥珀酸、[11 C]PHNO、[11 C]伏罗唑。这个新 发展的FMDS 11 C标记方法可能会在放射性示踪剂化学和开放 开发新的和实用的放射性标记方法的多种途径。

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.