New methods for carbon-11 radiotracer synthesis & application to NMDA PET imaging

碳11放射性示踪剂合成新方法

• 批准号: 7673318
• 负责人: Jacob M. Hooker
• 金额: $ 0.41万
• 依托单位: BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2009-11-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7673318
• 关键词: Address; Alkylating Agents; Animals; Aspartate; Biodistribution; Biological Availability; Brain; Brain Diseases; Bypass; Carbamates; Carbon; Carbon Dioxide; Carbonates; Chemicals; Chemistry; Complex; Coupling; Cyanides; Cyclization; Cyclotrons; Data; Development; Drug Kinetics; Equilibrium; Evaluation; Excitatory Amino Acid Antagonists; Functional disorder; Future; Heart; Human; Image; In Situ; In Vitro; Investigation; Kinetics; Label; Lead; Left; Literature; Medicine; Metabolic; Metabolism; Methods; Modeling; Molecular; Monitor; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurosciences; Nitrogen; Organ; Organic Synthesis; Papio; Papio anubis; Peripheral; Pharmaceutical Preparations; Phosgene; Positioning Attribute; Positron-Emission Tomography; Psychiatric therapeutic procedure; Radioactive; Radiolabeled; Rattus; Reaction; Research; Rodent; Screening procedure; Simulate; Site; Solutions; Solvents; Structure; Temperature; Tracer; Translational Research; addiction; chemical reaction; design; effective therapy; functional group; high throughput screening; human disease; in vivo; insight; interest; metabolic abnormality assessment; molecular imaging; nervous system disorder; novel; organic base; pharmacophore; piperidine; radiotracer; sample fixation; stoichiometry

DESCRIPTION (provided by applicant): Radiotracers have enabled investigations of molecular phenomena which are at the heart of understanding human disease and developing effective treatments. Yet, there exists a major deficiency in our ability to synthesize radiotracers. The focus of the research described herein is the development of new rapid chemical methods for the incorporation of readily available carbon-11 labeled precursors into common pharmacophore moieties for their use as radiotracers. The strategies are designed to target functional groups that are not adequately addressed by existing carbon-11 incorporation strategies. A particular focus is placed on radiolabeling compounds identified in the literature as candidates for the study and treatment of psychiatric and neurological disorders, with a special emphasis on addictive disorders. Specifically, the new chemical strategies we develop will be used to radiolabel a glutamate receptor antagonist. We will then evaluate the labeled compound as a radiotracer for positron emission tomography (PET).We will accomplish this in three specific aims. In Specific Aim 1, we will develop new rapid chemical reactions for the incorporation of carbon-11 into a) carbamate/carbonate functional groups and b) piperidine heterocycles. This will be accomplished by incorporating common [11C] labeling precursors, [11C]-carbon dioxide and [11C]-cyanide, using rapid organic synthesis. Carbonate and carbamate radiolabeling will be achieved by the direct chemical fixation of [11C]O2. Piperidine heterocycle labeling will be achieved through a novel reductive cyclization of 1,4-cyanoaldehydes prepared from [11C]N. In Specific Aim 2, we will evaluate these chemical strategies by radiolabeling a N-methyl-D-aspartate (NMDA) receptor antagonist. In Specific Aim 3, the radiolabeled antagonist will be evaluated as a radiotracer in vivo by PET. RELEVANCE: Advances in radiotracer chemistry and translational research directed to neurologicall targets involved in human brain dysfunction will accelerate the understanding of brain function and the development of effective treatments for brain disorders. The research proposed herein will advance radiotracer chemistry through the development of new methods for carbon-11 incorporation. These methods will be used for the synthesis of radiotracers to study brain dysfunction & neurological disorders.

描述（由申请人提供）：放射性示踪剂已经能够研究分子现象，这是理解人类疾病和开发有效治疗方法的核心。然而，我们合成放射性示踪剂的能力存在重大缺陷。本文所述研究的重点是开发新的快速化学方法，用于将易于获得的碳 11 标记前体掺入常用药效基团部分中，以用作放射性示踪剂。这些策略旨在针对现有碳 11 掺入策略未能充分解决的功能组。特别关注文献中确定的放射性标记化合物，作为研究和治疗精神和神经疾病的候选化合物，特别强调成瘾性疾病。具体来说，我们开发的新化学策略将用于放射性标记谷氨酸受体拮抗剂。然后，我们将评估标记化合物作为正电子发射断层扫描 (PET) 的放射性示踪剂。我们将通过三个具体目标来实现这一目标。在具体目标 1 中，我们将开发新的快速化学反应，将碳 11 掺入 a) 氨基甲酸酯/碳酸酯官能团和 b) 哌啶杂环中。这将通过使用快速有机合成结合常见的[11C]标记前体、[11C]-二氧化碳和[11C]-氰化物来实现。碳酸盐和氨基甲酸盐放射性标记将通过[11C]O2的直接化学固定来实现。哌啶杂环标记将通过由 [11C]N 制备的 1,4-氰基醛的新型还原环化来实现。在具体目标 2 中，我们将通过放射性标记 N-甲基-D-天冬氨酸 (NMDA) 受体拮抗剂来评估这些化学策略。在具体目标 3 中，放射性标记的拮抗剂将通过 PET 作为体内放射性示踪剂进行评估。相关性：放射性示踪剂化学和针对与人脑功能障碍相关的神经目标的转化研究的进展将加速对大脑功能的了解和开发针对脑部疾病的有效治疗方法。本文提出的研究将通过开发碳 11 掺入新方法来推进放射性示踪剂化学。这些方法将用于合成放射性示踪剂以研究脑功能障碍和神经系统疾病。

项目成果

Histone deacetylase inhibitor, MS-275, exhibits poor brain penetration: PK studies of [C]MS-275 using Positron Emission Tomography.

• DOI: 10.1021/cn9000268
• 发表时间: 2010
• 期刊: ACS CHEMICAL NEUROSCIENCE
• 影响因子: 5
• 作者: Hooker, Jacob M.;Kim, Sung Won;Alexoff, David;Xu, Youwen;Shea, Colleen;Reid, Alicia;Volkow, Nora;Fowler, Joanna S.
• 通讯作者: Fowler, Joanna S.

One-pot, direct incorporation of [11C]CO2 into carbamates.

• DOI: 10.1002/anie.200900112
• 发表时间: 2009
• 期刊: ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
• 影响因子: 16.6
• 作者: Hooker, Jacob M.;Reibel, Achim T.;Hill, Sidney M.;Schueller, Michael J.;Fowler, Joanna S.
• 通讯作者: Fowler, Joanna S.