PET Radiopharmaceutical Sciences

PET 放射性药物科学

• 批准号: 6982709
• 负责人: Victor W Pike
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6982709
• 关键词: amyloid proteins; bioimaging /biomedical imaging; brain imaging /visualization /scanning; carbon; chemical synthesis; dopamine transporter; fluorine; hormone receptor; mental disorder diagnosis; neuropsychology; positron emission tomography; radiochemistry; radionuclides; radiopharmacology; radiotracer; serotonin receptor; technology /technique development

The Molecular Imaging Branch (MIB) mainly aims to exploit positron emission tomography (PET) as a radiotracer imaging technique for investigating neuropsychiatric disorders, such as depression, schizophrenia and Alzheimer's disease. Fundamental to the mission of the MIB is the development of novel radiotracers that can be used with PET to deliver new and specific information on molecular entities and processes in the living human or animal brain (e.g. regional neuroreceptor concentrations, neurotransmitter synthesis, enzyme concentrations, regional metabolism, amyloid deposition). PET is uniquely powerful for this purpose provided that it can be coupled to appropriate radioactive probes (PET radiotracers). The chemical development of these probes is the key to exploiting the full potential of PET in neuropsychiatric research, but is also recognised as being highly challenging and demanding. The PET Radiopharmaceutical Sciences Section of the MIB opened in 2002 and is now established to fulfill the need for a concerted effort on PET radiotracer discovery (a process that has some parallels with drug discovery). The first phase of laboratories (~ 4000 sq ft) are equiped and functioning with state-of-the-art facilities for medicinal chemistry and automated radiochemistry with positron-emitting carbon-11 (t1/2 = 20 min) and fluorine-18 (t1/2 = 110 min). These short-lived radioisotopes must be produced on a daily basis from the adjacent cyclotrons of the NIH Clinical Center. A scientific program is now well established, focusing on developing novel radiotracers for brain receptors or proteins implicated in neuropsychiatric disorders [e.g. cannabinoid (CB-1), serotonin (5-HT1A), alpha-2, AMPA, CRH, NET, PBR, glutamate (mGluR5)and beta-amyloid protein deposits). Initial progress in some of these areas (e.g. NET, 5-HT1A, CB-1, PBR and glutamate)is already encouraging for eventual successful radioligand development. Thus many candidate radioligands were prepared and then found in PET experiments to give detectable receptor-specific signals in animals in vivo with PET. Methodology underpinning these developments was also advanced in areas such as polymer-supported labeling reactions, microwave-enhanced chemistry and radiochemistry and the development of micro-reactors for radiochemnistry. New analytical methods have also been developed and exploited to understand the biochemical fate of radiotracers - information which is need to fully understand the results from PET experiments and to derive meaningful merasures, such as brain receptor concentrations. Productive collaborations are established with external academic laboratories, and also with Pharma through a series of CRADAs (Cooperative Research and Development Agreements). The laboratory is already producing some radiotracers for regular PET investigations in animals {e.g. [18F]FECNT and [11C]PE2I (for dopamine transporter), [11C]NNC 112 (for dopamine-type-1 receptor), [18F]SPA-RQ (for NK1-receptor), [18F]Fallypride (for dopamine type-2 receptor imaging), [11C]Rolipram (for PDE4 enzyme)}and some of these are now available for brain imagimg in human subjects and clinical research protocols under FDA approved INDs. A second phase of laboratories (2000 sq ft), which will expand the facility for organic synthesis, radiochemistry and biological studies, is now planned.

分子成像分支（MIB）的主要目标是利用正电子发射断层扫描（PET）作为放射性示踪成像技术，用于研究神经精神疾病，例如抑郁症、精神分裂症和阿尔茨海默病。 MIB 使命的基础是开发新型放射性示踪剂，这些示踪剂可与 PET 一起使用，提供有关活人或动物大脑中分子实体和过程的新的特定信息（例如区域神经受体浓度、神经递质合成、酶浓度、区域代谢、淀粉样蛋白沉积）。 PET 对于此目的具有独特的功能，只要它可以与适当的放射性探针（PET 放射性示踪剂）结合即可。这些探针的化学开发是在神经精神病学研究中充分发挥 PET 潜力的关键，但也被认为具有很高的挑战性和要求。 MIB 的 PET 放射性药物科学部于 2002 年成立，现在成立是为了满足 PET 放射性示踪剂发现（这一过程与药物发现有一些相似之处）的共同努力的需要。第一期实验室（约 4000 平方英尺）配备并运行最先进的药物化学和自动放射化学设施，其中包括正电子发射碳 11（t1/2 = 20 分钟）和氟 18（ t1/2 = 110 分钟）。这些短寿命放射性同位素必须每天从 NIH 临床中心的相邻回旋加速器产生。 一项科学计划现已完善，重点是开发与神经精神疾病有关的大脑受体或蛋白质的新型放射性示踪剂。大麻素 (CB-1)、血清素 (5-HT1A)、α-2、AMPA、CRH、NET、PBR、谷氨酸 (mGluR5) 和 β-淀粉样蛋白沉积物）。其中一些领域（例如 NET、5-HT1A、CB-1、PBR 和谷氨酸）的初步进展对于最终成功开发放射性配体已经令人鼓舞。因此，制备了许多候选放射性配体，然后在 PET 实验中发现，用 PET 在动物体内提供可检测的受体特异性信号。支持这些发展的方法论在聚合物支持的标记反应、微波增强化学和放射化学以及放射化学微反应器的开发等领域也取得了进展。新的分析方法也已被开发和利用来了解放射性示踪剂的生化命运，这些信息是充分了解 PET 实验结果并得出有意义的测量结果（例如脑受体浓度）所必需的。我们与外部学术实验室以及制药公司通过一系列 CRADA（合作研究与开发协议）建立了富有成效的合作。 该实验室已经在生产一些放射性示踪剂，用于动物的常规 PET 研究（例如动物）。 [18F]FECNT 和 [11C]PE2I（用于多巴胺转运蛋白）、[11C]NNC 112（用于多巴胺 1 型受体）、[18F]SPA-RQ（用于 NK1 受体）、[18F]Fallypride（用于多巴胺） 2 型受体成像）、[11C]咯利普兰（用于 PDE4 酶）}其中一些现已可用于大脑imagimg 在人类受试者中的应用以及 FDA 批准的 IND 下的临床研究方案。目前正在规划第二期实验室（2000 平方英尺），该项目将扩大有机合成、放射化学和生物研究的设施。