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: 6737496
• 负责人: SALVATORE D LEPORE
• 金额: $ 7.03万
• 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/6737496
• 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（由申请人提供）：正电子发射断层扫描（PET）是一种强大的工具，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 PET 研究涉及使用 11C 标记的 PET 示踪剂。由于 11C 同位素的半衰期较短（20 分钟），如果示踪剂要保留足够的无线电发射特性以用作显像剂，则必须在极短的时间内合成 11C-PET 示踪剂。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。在本提案中，我们概述了一种新型固相技术的开发，该技术应显着加快 11C-PET 示踪剂的合成，并应在各种治疗领域（包括脑成像）中找到应用。在我们提出的方法中，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。该反应顺序应导致形成所需的 11C-PET 示踪剂作为唯一产物。因此，这种基于树脂的策略旨在避免传统的反应纯化步骤，从而为合成 PET 示踪剂留出更多时间，与以前相比，该示踪剂具有潜在更高的特异性放射性和更大的分子复杂性。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 示踪剂的生产率。我们还建议在两种γ-丁酸（GABA）受体激动剂11C-GABOB和11C-巴氯芬的首次11C合成中采用这种新方法。 CABOB 已被用于治疗癫痫，而巴氯芬广泛用于治疗多发性硬化症、抽动秽语综合征和肌张力障碍所表现的痉挛。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大大加深我们对这些药物的理解，并有可能导致治疗中枢神经系统疾病的新疗法的开发。