PET Radiopharmaceutical Sciences

PET 放射性药物科学

• 批准号: 7969360
• 负责人: Victor W Pike
• 金额: $ 386.22万
• 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/7969360
• 关键词: Alcoholism; Alzheimer' s Disease; Amyloid beta-Protein; Amyloid deposition; Animals; Anxiety; Area; Atherosclerosis; Autistic Disorder; Behavior; Binding Sites; Biochemical; Biochemical Process; Biological Markers; Blood; Blood - brain barrier anatomy; Brain; Brain imaging; Cannabinoids; Cannabis; Carbon; Carbon Radioisotopes; Chemicals; Chemistry; Clinical; Clinical Research; Cocaine Dependence; Collaborations; Cooperative Research and Development Agreement; Coupled; Cyclotrons; Dementia; Deposition; Development; Diagnosis; Disease; Doctor of Philosophy; Dopamine D1 Receptor; Dopamine D2 Receptor; Drug Addiction; Drug Efflux; Engineering; Enzymes; Evaluation; Fluorine; Foundations; Fragile X Syndrome; Generic Drugs; Glutamates; Goals; Half-Life; Human; Image; Imaging Techniques; Inflammation; Inflammatory; Institution; International; Investigation; Investigational New Drug Application; Label; Laboratories; Life; Liquid Chromatography; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Measurement; Measures; Metabolism; Methodology; Methods; Microfluidics; Mind; Miniaturization; Mission; Modeling; Molecular; Multi-Drug Resistance; Names; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Neurotransmitter Receptor; Neurotransmitters; Obesity; Organism; Output; Parkinson Disease; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Physics; Positron; Positron-Emission Tomography; Procedures; Process; Production; Proteins; Publishing; Radio; Radioactive; Radioactivity; Radiochemistry; Radioisotopes; Radiolabeled; Radiopharmaceuticals; Reporting; Research; Research Support; Risk; Role; Rolipram; Schizophrenia; Science; Scientist; Sensory Receptors; Serotonin; Serotonin Receptor 5-HT1A; Serotonin Receptor 5-HT1B; Site; Stroke; Techniques; Training; Traumatic Brain Injury; United States Food and Drug Administration; United States National Institutes of Health; Universities; Work; addiction; analytical method; base; depression; design; drug development; drug discovery; efflux pump; human subject; imaging probe; improved; insight; interest; intravenous administration; molecular imaging; neuropsychiatry; news; novel; phosphodiesterase IV; programs; 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, addiction, schizophrenia and Alzheimer's disease. Fundamental to the mission of the MIB is the development of novel radioactive probes (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, drug efflux from brain). PET is uniquely powerful for this purpose, provided that it can be coupled to the use of appropriate 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 a highly challenging and demanding scientific task. Our laboratory, the PET Radiopharmaceutical Sciences Section of the MIB, places a concerted effort on PET radiotracer discovery (a process that has some parallels with drug discovery in terms of required effort and risk). The laboratories are equipped with modern facilities for performing medicinal chemistry and automated radiochemistry with positron-emitting carbon-11 (t1/2 = 20 min) and fluorine-18 (t1/2 = 110 min). The two short-lived radioisotopes needed to support this research program are produced on a daily basis from the adjacent cyclotrons of the NIH Clinical Center. Our scientific program currently focuses on developing novel probes for imaging and quantifying a number of different brain receptors or proteins implicated in neuropsychiatric disorders e.g., cannabinoid (CB-1) (9-13, 30, 42-44), serotonin (5-HT1A, 5-HT4) (27,31), TSPO (formerly known as PBR) (1,2,15,16,18,20), and glutamate (mGluR1,mGluR5) (3,37) receptors, efflux transporters (P-gp) (22,24,34,45) and protein deposits such as beta-amyloid (4,36). Progress in some of these areas has already been successful, providing new radiotracers for CB-1 (10,11,30,42-44), TSPO (1,2,15,16,18,20), mGluR5 (3,37) and P-gp (22,24,34,45) for brain imaging in human subjects in support of clinical research. This research is conducted under Food and Drug Administration (FDA) oversight through 'exploratory' or full investigational new drug applications (expINDs or INDs). Many candidate radiotracers were designed, prepared and evaluated in reaching these goals. Two radiotracers developed for TSPO imaging ((C-11)PBR28 (1) and (F-18)FBR (2)) appear highly successful and are starting to have application for the investigation of brain inflammatory conditions in response to neurological insults e.g., traumatic brain injury, stroke and neurodegeneration. Production of these radiotracers is now being set up by other institutions (e.g., Cambridge University, Pitsburgh University) to perform clinical studies. CB-1 receptors are the sites in the brain that are acted upon by cannabis. Our new CB-1 radiotracers ((C-11)MePPEP, (F-18)FMPEP) (10) have potential for the study of drug addiction, including alcoholism and cocaine addiction. These probes may also have relevance to the study of other disorders, such as obesity. (C-11)MEPPEP has entered use elsewhere. Our mGluR radiotracer ((F-18)SP203 (3)) is expected to have value for the study of Fragile X syndrome, addiction, autism and schizophrenia. Such PET radiotracers have additional value in expediting drug discovery (see for example the recent popular feature article entitled 'A Chemical Map of The Mind - Targeted radiotracers help drug makers navigate the neurological landscape by PET', published in Chemistry and Engineering News, Sep 8th, 2008, which discusses our mGluR radiotracer and other probes. The imaging of drug efflux pumps (e.g., P-gp) at the blood-brain barrier is a recent area of interest in our laboratory with relevance to drug development for neuropsychiatric disorders. We have developed a much improved radiotracer, named (C-11)dLop (22), for this purpose, which has now reached the level of study in human subjects (34,35). This radiotracer is now also being produced at other centers. (C-11)dLop has clinical research potential for assessing the role of efflux pumps in Alzheimer's disease and other neurodegenerative disorders (e.g., Parkinson's disease). Some of the radiotracers that we have developed are likely to have value for diseases that present outside the brain. Thus, the TSPO radiotracers may be generic for the study of inflammation in the periphery (e.g., as occurs in atherosclerosis), and the P-gp radiotracer for the study of cancer (especially multi-drug resistance). 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, MD, PhD). Methodology underpinning our radiotracer development was also advanced in areas such as the development of new synthetic methods (8,17,28,38,41), new radiolabeling procedures (26,31,40), and the application of micro-reactors to the miniaturization of radiochemistry (25). Over the past year, we have combined the use of microfluidics with a new F-18 labeling strategy to great effect, so expanding the number and type of candidate F-18 labeled radiotracers that may be produced. Such advances are seen as being vital for facilitating radiotracer applications. New analytical methods, based on for example liquid chromatography coupled to mass spectrometry (LC-MS), have also been developed and exploited to understand the biochemical fate of radiotracers in living systems (32,37). This information is needed to fully understand the results from PET experiments and to derive meaningful output measures, such as brain receptor concentrations. Sensitive LC-MS has been introduced for the measurement of radiotracer half-life and specific radioactivity, and also for the measurement of radiotracer concentration in blood following intravenous administration. The use of LC-MS avoids the need to measure fast-decaying radioactivity. Productive collaborations have been established with external academic chemistry and medicinal chemistry laboratories, nationally and internationally, and also with pharmaceutical companies through CRADAs (Cooperative Research and Development Agreements) and the Biomarker Consortium of the Foundation for NIH. Productive collaborations also exist with other centers working with PET and its associated radiochemistry and radiotracer development. The laboratory is active in training new scientists for this field at all levels. In addition, we produce several established radiotracers for PET investigations in animal or human subjects e.g.,(F-18)SPA-RQ (for NK1 receptor imaging)(14), (C-11)NNC 112 (D1 receptor imaging) (6), (F-18)fallypride (D2 receptor imaging) (7,25), (C-11)MNPA (functional D2 receptor imaging) (33,35,40), (C-11)CUMI (5-HT1A receptor imaging), (C-11)AZ (5-HT1B receptor imaging), (C-11)MeNER (noradrenalin transporter imaging)(32), (C-11)rolipram (PDE4 enzyme imaging) (19,39), and (C-11)PK 11195 (TSPO binding site imaging). The production of such radiotacers for use in in human subjects complies with (Food and drug Administration) FDA requirements under exploratory or full Investigational New Drug applications (INDs). Each PET experiment with one of these radiotracers requires a radiosynthesis of the radiotracer on the same day, and hence radiotracer production is a regular activity. Approximately 400 productions are performed per annum.

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，如抑郁症、成瘾、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探针（放射性示踪剂），这些探针可与 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、药物从大脑流出）。 PET 对于此目的具有独特的功能，只要它可以与适当的 PET 放射性示踪剂的使用相结合。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，但也被广泛认为是一项极具挑战性和高要求的科学任务。 我们的实验室（MIB 的 PET 放射性药物科学部）致力于 PET 放射性示踪剂的发现（这一过程在所需的努力和风险方面与药物发现有一些相似之处）。实验室配备了现代化的设施，可使用正电子发射碳 11（t1/2 = 20 分钟）和氟 18（t1/2 = 110 分钟）进行药物化学和自动放射化学。支持该研究计划所需的两种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。 我们的科学计划目前专注于开发新型探针，用于成像和量化与神经精神疾病有关的许多不同的大脑受体或蛋白质，例如大麻素 (CB-1) (9-13, 30, 42-44)、血清素 (5-HT1A) , 5-HT4) (27,31), TSPO（以前称为 PBR） (1,2,15,16,18,20) 和谷氨酸 (mGluR1,mGluR5) (3,37) 受体、外排转运蛋白 (P-gp) (22,24,34,45) 和蛋白质沉积物，例如 β -淀粉样蛋白（4,36）。其中一些领域的进展已经取得成功，为 CB-1 (10,11,30,42-44)、TSPO (1,2,15,16,18,20)、mGluR5 (3,37) 提供了新的放射性示踪剂) 和 P-gp (22,24,34,45) 用于人类受试者的脑成像以支持临床研究。这项研究是在美国食品药品监督管理局 (FDA) 的监督下通过“探索性”或全面研究性新药申请（expIND 或 IND）进行的。为了实现这些目标，设计、准备和评估了许多候选放射性示踪剂。为 TSPO 成像开发的两种放射性示踪剂（(C-11)PBR28 (1) 和 (F-18)FBR (2)）似乎非常成功，并开始应用于研究神经损伤引起的脑炎症状况，例如，外伤性脑损伤、中风和神经退行性疾病。其他机构（例如剑桥大学、匹兹堡大学）目前正在生产这些放射性示踪剂以进行临床研究。 CB-1 受体是大脑中大麻作用的部位。我们的新型 CB-1 放射性示踪剂 ((C-11)MePPEP、(F-18)FMPEP) (10) 具有研究药物成瘾的潜力，包括酗酒和可卡因成瘾。这些探针也可能与其他疾病的研究相关，例如肥胖症。 (C-11)MEPPEP 已在其他地方使用。我们的 mGluR 放射性示踪剂 ((F-18)SP203 (3)) 预计对脆性 X 综合征、成瘾、自闭症和精神分裂症的研究具有价值。这种 PET 放射性示踪剂在加速药物发现方面具有额外的价值（例如，参见最近流行的专题文章，题为“思维化学地图 - 靶向放射性示踪剂帮助制药商通过 PET 导航神经学景观”，发表在化学与工程新闻，9 月 8 日） ，2008 年，其中讨论了我们的 mGluR 放射性示踪剂和其​​他探针在血脑屏障处的药物流出泵（例如 P-gp）的成像。我们实验室最近感兴趣的领域与神经精神疾病的药物开发相关，为此我们开发了一种改进的放射性示踪剂，名为 (C-11)dLop (22)，目前已达到人类受试者的研究水平。 (34,35) 这种放射性示踪剂现在也在其他中心生产，具有评估外排泵在阿尔茨海默病和其他神经退行性疾病中的作用的临床研究潜力。 （例如，帕金森病）。 我们开发的一些放射性示踪剂可能对大脑外部的疾病有价值。因此，TSPO 放射性示踪剂可通用用于研究外周炎症（例如，动脉粥样硬化中发生的炎症），而 P-gp 放射性示踪剂可通用用于研究癌症（尤其是多重耐药性）。 所有影像研究都是通过与分子影像科影像科（科科长、R.B. Innis 博士、医学博士、博士）密切的多学科互动来进行。 支持我们放射性示踪剂开发的方法学在新合成方法的开发 (8,17,28,38,41)、新放射性标记程序 (26,31,40) 以及微反应器在放射化学的小型化（25）。在过去的一年里，我们将微流体的使用与新的 F-18 标记策略相结合，取得了巨大的效果，从而扩大了可能生产的候选 F-18 标记放射性示踪剂的数量和类型。 这些进步被认为对于促进放射性示踪剂的应用至关重要。基于例如液相色谱与质谱联用 (LC-MS) 的新分析方法也已被开发和利用，以了解生命系统中放射性示踪剂的生化命运 (32,37)。 需要这些信息来充分理解 PET 实验的结果并得出有意义的输出测量值，例如大脑受体浓度。灵敏的 LC-MS 已被引入用于测量放射性示踪剂半衰期和比放射性，以及测量静脉注射后血液中放射性示踪剂的浓度。 使用 LC-MS 无需测量快速衰减的放射性。 我们与国内外的外部学术化学和药物化学实验室以及通过 CRADA（合作研究与开发协议）和 NIH 基金会生物标志物联盟与制药公司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。 该实验室积极培养该领域各个级别的新科学家。 此外，我们还生产几种已确定的放射性示踪剂，用于动物或人类受试者的 PET 研究，例如(F-18)SPA-RQ（用于 NK1 受体成像）(14)、(C-11)NNC 112（D1 受体成像）(6 ), (F-18)fallypride（D2 受体成像） (7,25), (C-11)MNPA（功能性 D2 受体成像） (33,35,40)、(C-11)CUMI（5-HT1A 受体成像）、(C-11)AZ（5-HT1B 受体成像）、(C-11)MeNER（去甲肾上腺素转运蛋白成像）(32) 、(C-11)咯利普兰（PDE4 酶成像）(19,39) 和 (C-11)PK 11195（TSPO 结合位点成像）。此类用于人类受试者的放射性标记物的生产符合（食品和药物管理局）FDA 在探索性或全面研究性新药申请 (IND) 下的要求。 使用这些放射性示踪剂之一进行的每次 PET 实验都需要在同一天进行放射性示踪剂的放射合成，因此放射性示踪剂的生产是一项常规活动。 每年演出约 400 部作品。