New Methods for the Expedited Synthesis of C11 and F18 PET Tracers

快速合成 C11 和 F18 PET 示踪剂的新方法

基本信息

批准号：
8660825
负责人：
SALVATORE D LEPORE
金额：
$ 5.51万
依托单位：
FLORIDA ATLANTIC UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-19 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8660825
关键词：
Address Affinity Alcohols Arylsulfonates Baclofen Binding Brain Brain Diseases Brain imaging Butyric Acids Carboxylic Acids Cations Chemistry Chromatography Cyanides Cyclotrons Development Disease Dystonia Epilepsy Exhibits Florida Fluorides Future GABA Agonists GABA Receptor Gilles de la Tourette syndrome Goals Growth Image Imaging Techniques Isotopes Label Laboratories Lead Left Medical Metal exposure Metals Methodology Methods Molecular Molecular Probes Multiple Sclerosis National Institute of Mental Health Neuromodulator Nitriles Organic Synthesis Patients Performance Phase Pike fish Polymers Positron Positron-Emission Tomography Potassium Cyanide Preparation Process Property Radio Radioisotopes Reaction Reagent Reporting Research Personnel Salts Series Side Solid Solutions Solvents Speed Staging System Techniques Technology Temperature Tetrazoles Time Tracer Training Travel Universities Work analog base chemical reaction design doctoral student gamma-Aminobutyric Acid high risk imaging probe improved molecular imaging novel potassium fluoride public health relevance radiochemical reaction rate receptor small molecule

项目摘要

DESCRIPTION (provided by applicant): Compounds labeled with positron-emitting isotopes 18F and 11C have found powerful applications as tracers for positron emission tomography (PET). These molecular probes have become indispensable for understanding the mechanisms of both normal brain function and brain disorders. Due to the short half-lives of these radioisotopes, the synthesis and purification of 18F- and especially 11C-tracers must be performed with extreme rapidity if they are to retain sufficient radio-emitting properties to be useful as imaging agents. Thus the growth of the PET technique has been closely tied to the development of new rapid-synthesis and purification methods. In this revised proposal, we outline a paradigm shift in radiosynthesis methodology by focusing on the development of a new class of reactive entities that are uniquely activated by metal cations that form part of the nuclide salts most often used in the synthesis of PET agents (e.g. K18F and K11CN). This new reactive system termed nucleophile assisting leaving group (NALG) is expected to significantly expedite the radiosynthesis of imaging agents and limit side-product formation. In our proposed approach, a PET tracer precursor is covalently attached to a polymer support that has been modified to contain the new reactive entity (the NALG). In a second step, cyclotron-derived fluoride or cyanide are added to the polymer resulting in the formation of the desired radio labeled tracer as the only product. In addition to increased reaction rates, this unprecedented strategy has been designed to avoid byproduct formation and minimize the time required for reaction purification. Taken together, these reaction improvements are expected to leave more time for the synthesis of imaging probes with potentially higher specific activities and greater molecular complexity than previously possible. We will employ this new NALG polymer method in the first synthesis of [11C]baclofen, a 3- amino-butyric acid (GABA) receptor agonist. As a well known probe for targeting GABAB, baclofen is widely- used for the management of spasticity exhibited in multiple sclerosis, Tourette syndrome, and dystonia. Made possible by the new polymer-based method, the efficient radio synthesis of [11C] baclofen (and related analogs for better brain permeation) is expected to facilitate future PET studies of GABA receptors and ultimately lead to improved therapies for diseases related to these receptors.

描述（由申请人提供）：用正电子发射同位素 18F 和 11C 标记的化合物已发现作为正电子发射断层扫描（PET）示踪剂的强大应用。这些分子探针对于了解正常大脑功能和大脑疾病的机制已变得不可或缺。由于这些放射性同位素的半衰期较短，18F-尤其是11C-示踪剂的合成和纯化必须极其快速地进行，如果它们要保留足够的放射性发射特性以用作成像剂。因此，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。在这个修订后的提案中，我们概述了放射合成方法的范式转变，重点是开发一类新型反应实体，这些实体只能被金属阳离子激活，这些金属阳离子构成最常用于合成 PET 试剂的核素盐的一部分（例如， K18F 和 K11CN）。这种被称为亲核辅助离去基团（NALG）的新反应系统预计将显着加速显像剂的放射合成并限制副产物的形成。在我们提出的方法中，PET 示踪剂前体共价连接到经过修饰以包含新反应实体（NALG）的聚合物载体上。在第二步中，将回旋加速器衍生的氟化物或氰化物添加到聚合物中，从而形成所需的放射性标记示踪剂作为唯一的产物。除了提高反应速率之外，这种前所未有的策略还旨在避免副产物的形成并最大限度地减少反应纯化所需的时间。总而言之，这些反应的改进预计将为成像探针的合成留下更多的时间，这些探针具有比以前更高的比活性和更大的分子复杂性。我们将采用这种新的 NALG 聚合物方法首次合成[11C]巴氯芬，一种 3-氨基丁酸 (GABA) 受体激动剂。作为一种众所周知的靶向 GABAB 的探针，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中表现出的痉挛状态。通过新的基于聚合物的方法，[11C]巴氯芬（以及具有更好的脑渗透性的相关类似物）的有效放射合成成为可能，预计将促进未来 GABA 受体的 PET 研究，并最终改进与这些受体相关的疾病的治疗方法。