Solid-Phase Approach to the Synthesis of CII PET Tracers

CII PET 示踪剂的固相合成方法

• 批准号: 7035564
• 负责人: SALVATORE D LEPORE
• 金额: $ 5.48万
• 依托单位: FLORIDA ATLANTIC UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7035564
• 关键词: GABA receptor; bioimaging /biomedical imaging; brain imaging /visualization /scanning; carbon; cyanides; high performance liquid chromatography; hydrogen; particle accelerators; positron emission tomography; radionuclides; radiotracer; resin; stimulant /agonist; technology /technique development

DESCRIPTION (provided by applicant): Positron emission tomography (PET) is a powerful tool that utilizes radioisotope-labeled molecules (PET tracers) to study the biochemistry and distribution of these molecules in the human brain. A considerable fraction of PET studies involve the use of 11C-labeled PET tracers. Due to the short half-life of the 11C-isotope (20 minutes), the synthesis of 11C-PET tracers must be preformed in an extremely short timeframe if the tracer is to retain sufficient radio-emitting properties to be useful as an imaging agent. Thus the growth of the 11C-PET technique has been closely tied to the development of new rapid synthesis and purification methods. In this proposal, we outline the development of a novel solid-phase technique that should significantly expedite the synthesis of 11C-PET tracers that should find application in a wide variety of therapeutic areas (including brain imaging). In our proposed approach, a PET tracer precursor is covalently attached to a designed polymer resin followed by the addition of cyclotron-derived hydrogen cyanide. This reaction sequence should result in the formation of the desired 11C-PET tracer as the only product. Thus, this resin-based strategy has been designed to avoid the traditional reaction purification step, leaving more time for the synthesis of PET tracers with potentially higher specific radioactivities and greater molecular complexity than previously possible. Based on various hypotheses on the mechanism of the cyanide addition reaction, a series of resins have been designed to maximize the rate of 11C-PET-tracer production. We also propose to employ this new methodology in the first 11C-synthesis of two gamma-butyric acid (GABA) receptor agonists 11C-GABOB and 11C-baclofen. CABOB has been prescribed for the treatment of epilepsy and baclofen is widely-used for the management of spasticity exhibited in multiple sclorosis, Tourette Syndrome, and dystonia. The creation of radioisotope-labeled analogs of CABOB and baclofen for PET studies should significantly further our understanding of these drugs and potentially lead to the development of new therapies for treating central nervous system diseases.

描述(申请人提供)：正电子发射断层扫描(PET)是一个强大的工具，它利用放射性同位素标记的分子(PET示踪剂)来研究这些分子在人脑中的生物化学和分布。相当一部分的正电子发射计算机断层扫描研究涉及使用11C标记的正电子发射体示踪剂。由于11C-同位素的半衰期很短(20分钟)，11C-PET示踪剂的合成必须在极短的时间内进行，如果示踪剂要保持足够的放射性发射性能以用作显像剂。因此，11C-PET技术的发展与新的快速合成和纯化方法的发展密切相关。在这项提案中，我们概述了一种新的固相技术的发展，该技术将显著加快11C-PET示踪剂的合成，该示踪剂将在广泛的治疗领域(包括脑成像)中得到应用。在我们提出的方法中，将PET示踪剂前体共价连接到设计的聚合物树脂上，然后添加回旋加速器衍生的氰化氢。该反应序列应能形成所需的11C-PET示踪剂作为唯一产物。因此，这种基于树脂的策略被设计为避免了传统的反应纯化步骤，为合成具有潜在更高比放射性和更大分子复杂性的PET示踪剂留出了更多的时间。基于对氰化物加成反应机理的各种假设，设计了一系列树脂，以最大限度地提高11C-PET示踪剂的生产速度。我们还建议将这一新方法用于两种伽马丁酸(GABA)受体激动剂11C-GABOB和11C-巴氯芬的首次11C合成。CABOB已被用于治疗癫痫，巴氯芬被广泛用于治疗多发性硬化症、多发性抽动症和肌张力障碍的痉挛。用于PET研究的放射性同位素标记的CABOB和巴氯芬类似物的创建将极大地加深我们对这些药物的理解，并可能导致治疗中枢神经系统疾病的新疗法的开发。