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

描述(申请人提供)：放射性示踪剂使对分子现象的研究成为可能，而分子现象是了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一个重大缺陷。本文描述的研究重点是开发新的快速化学方法，用于将容易获得的碳-11标记前体结合到常见的药效团部分中，以用作放射性示踪剂。这些战略旨在针对现有的碳-11掺入战略没有充分解决的官能团。一个特别的重点放在文献中确定的用于精神和神经障碍的研究和治疗的放射性标记化合物上，特别强调成瘾障碍。具体地说，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点。在具体目标1中，我们将开发新的快速化学反应，将碳-11结合到a)氨基甲酸酯/碳酸酯官能团和b)哌啶杂环中。这将通过加入常见的[11C]标记前体[11C]-二氧化碳和[11C]-氰化物，使用快速有机合成来实现。碳酸盐和氨基甲酸酯的放射性标记将通过[11C]O2的直接化学固定来实现。从[11C]N制备的1，4-氰醛将通过一种新的还原环化反应来实现哌啶杂环标记。在特定的目标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。在特定的目标3中，放射性标记的拮抗剂将作为体内的放射性示踪剂进行正电子发射计算机断层扫描。相关性：针对神经学的放射性示踪化学和翻译研究的进展将促进对大脑功能的了解和开发有效的脑部疾病治疗方法。本文提出的研究将通过开发碳-11掺入的新方法来促进放射性示踪化学的发展。这些方法将用于合成放射性示踪剂，以研究大脑功能障碍和神经疾病。

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.