PET Radiopharmaceutical Sciences

PET 放射性药物科学

• 批准号: 7594543
• 负责人: Victor W Pike
• 金额: $ 352.96万
• 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/7594543
• 关键词: Alzheimer' s Disease; Amyloid beta-Protein; Amyloid deposition; Animals; Area; Biochemical; Blood; Brain; Brain imaging; Cannabinoids; Carbon; Carbon Radioisotopes; Chemicals; Chemistry; Clinical; Clinical Research; Clinical Research Protocols; Collaborations; Condition; Cooperative Research and Development Agreement; Coupled; Cyclotrons; Daily; Deposition; Development; Disease; Dopamine; Drug Efflux; Enzymes; Fluorine; Glutamates; Half-Life; Health; Human; Image; Imaging Techniques; Inflammatory; International; Investigation; Label; Laboratories; Life; Liquid Chromatography; Malignant Neoplasms; Mass Spectrum Analysis; Measures; Mental Depression; Metabolism; Methodology; Miniaturization; Mission; Molecular; Nerve Degeneration; Neurologic; Neurotransmitters; Organic Chemistry; Pharmaceutical Chemistry; Pharmacologic Substance; Pharmacology; Polymers; Positron; Positron-Emission Tomography; Process; Proteins; Purpose; Radio; Radioactive; Radiochemistry; Radioisotopes; Radiopharmaceuticals; Range; Reaction; Research; Schizophrenia; Science; Sensory Receptors; Series; Serotonin; Serotonin Receptor 5-HT1A; Signal Transduction; Site; Stroke; Support of Research; Techniques; United States Food and Drug Administration; United States National Institutes of Health; Work; analytical method; base; drug development; drug discovery; efflux pump; human subject; improved; in vivo; insight; interest; microwave electromagnetic radiation; molecular imaging; neuropsychiatry; novel; phosphodiesterase IV; programs; radioligand; radiotracer; receptor; research study; response

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 animal or human 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 widely recognized as being highly challenging and demanding. The PET Radiopharmaceutical Sciences Section of the MIB opened in August 2002 and is now fulfilling a pressing need for a concerted effort on PET radiotracer discovery (a process that has some parallels with drug discovery). The laboratories are equipped and functioning with modern facilities for medicinal/organic chemistry and automated radiochemistry with positron-emitting carbon-11 (t1/2 = 20 min) and fluorine-18 (t1/2 = 110 min). These short-lived radioisotopes are produced on a daily basis from the adjacent cyclotrons of the NIH Clinical Center in support of this research program. The scientific program focuses on developing novel radiotracers for brain receptors or proteins implicated in neuropsychiatric disorders e.g. cannabinoid (CB-1), serotonin (5-HT1A), alpha-2, NET, PBR, glutamate (mGluR5) and beta-amyloid protein deposits. Progress in some of these areas (e.g. NET, 5-HT1A, CB-1, PBR and mGluR5) continues to be encouraging for developing successful radioligands for eventual brain imaging in human subjects in support of clinical research. Thus many candidate radioligands were prepared and then found in PET experiments to give detectable receptor-specific signals in animals in vivo with PET. Imaging of brain 5-HT1A receptors and PBR with new radioligands has now commenced in human subjects under FDA approval through exploratory INDs. Radiotracers developed for PBR appear highly successful and are destined to have broad application for the investigation of brain inflammatory conditions in response to neurological insults e.g. stroke, neurodegeneration. Similar FDA approvals have been gained for imaging, beta-amyloid, CB1 and mGluR5 targets with newly developed radiotracers. The imaging of drug efflux pumps at the blood-barin barrier is a new area of interest with relavance to drug development ro neuropsychaitric diosorders and cancer. A much improved radiotracer has been developed for this purpose. Approval is now sought fromthe FDA for use of this radiotracer in human subjects.All imaging studies are performed through close multi-disciplinary interaction with the Imaging Section of the Molecular Imaging Branch (Chief of Section and Branch, Dr. R.B. Innis). Methodology underpinning these developments was also advanced in areas such as the development of new radioactive labeling agents, polymer-supported labeling reactions, microwave-enhanced chemistry and radiochemistry, and the development of micro-reactors for the miniaturization of radiochemistry. These advances are seen as vital for expanding the scope for generating new radiotracers and for facilitating their applications. New analytical methods, based on for example liquid chromatography coupled to mass spectrometry, have also been developed and exploited to understand the biochemical fate of radiotracers in vivo - information which is need to fully understand the results from PET experiments and to derive meaningful measures, such as brain receptor concentrations. Productive collaborations have been established with external academic chemistry and medicinal chemistry laboratories, nationally and internationally, and also with pharmaceutical companies through a series of CRADAs (Cooperative Research and Development Agreements). Productive collaborations also exist with other centers working with PET and its associated radiochemistry and radiotracer development. This laboratory also produces several radiotracers for regular PET investigations in animals e.g. 11CNNC 112 (18FSPA-RQ (for NK1-receptor), 18FFallypride (for dopamine type-2 receptor imaging), 11CRolipram (for PDE4 enzyme) and some of these have been approved by the FDA and are available for brain imaging in human subjects and clinical research protocols.

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，提供有关活体动物或人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，但也被广泛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 8 月成立，目前正在满足 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）方面共同努力的迫切需要。实验室配备了现代化的药物/有机化学和自动放射化学设施，可发射正电子碳 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每天由 NIH 临床中心的相邻回旋加速器产生，以支持该研究计划。 该科学计划的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、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 mGluR5）的进展继续令人鼓舞，有助于开发成功的放射性配体，用于人类受试者的最终脑成像，以支持临床研究。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。在 FDA 通过探索性 IND 批准后，使用新放射性配体对大脑 5-HT1A 受体和 PBR 进行成像现已开始在人类受试者中进行。为 PBR 开发的放射性示踪剂似乎非常成功，并且注定会在研究神经损伤（例如，神经损伤）引起的脑炎症状况方面具有广泛的应用。中风、神经退行性疾病。新开发的放射性示踪剂的成像、β-淀粉样蛋白、CB1 和 mGluR5 靶点也获得了 FDA 的类似批准。血巴蛋白屏障处药物流出泵的成像是一个新的令人感兴趣的领域，与神经精神疾病和癌症的药物开发相关。为此目的，开发了一种经过大幅改进的放射性示踪剂。 目前正在寻求 FDA 批准在人类受试者中使用这种放射性示踪剂。所有成像研究都是通过与分子成像部门的成像部门（部门和部门负责人 R.B. Innis 博士）密切的多学科互动来进行。 支持这些发展的方法学在新型放射性标记剂的开发、聚合物支持的标记反应、微波增强化学和放射化学以及用于放射化学小型化的微反应器的开发等领域也取得了进展。这些进步被认为对于扩大新放射性示踪剂的产生范围和促进其应用至关重要。新的分析方法，例如基于液相色谱与质谱联用的分析方法，也已被开发和利用，以了解放射性示踪剂在体内的生化命运 - 需要充分了解 PET 实验结果并得出有意义的测量结果的信息，例如作为脑受体浓度。 我们与国内外学术化学和药物化学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。还与其他从事 PET 及其相关放射化学和放射性示踪剂开发的中心开展富有成效的合作。 该实验室还生产多种放射性示踪剂，用于动物的常规 PET 研究，例如动物。 11CNNC 112（18FSPA-RQ（用于 NK1 受体）、18FFallypride（用于多巴胺 2 型受体成像）、11CRolipram（用于 PDE4 酶），其中一些已获得 FDA 批准，可用于人类受试者的脑成像，临床研究协议。