PET Radiopharmaceutical Sciences

PET 放射性药物科学

• 批准号: 8158099
• 负责人: Victor W Pike
• 金额: $ 401.15万
• 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/8158099
• 关键词: Positron-Emission Tomography; Radiopharmaceuticals; Science

The Molecular Imaging Branch (MIB) 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 and sensitive 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. Potential imaging targets far exceed the range of probes available. Our laboratory, the PET Radiopharmaceutical Sciences Section of the MIB, places a concerted effort on PET radiotracer discovery. This process has some parallels with drug discovery in terms of required effort and risk, because successful probes must fulfill a difficult-to-satisfy range of chemical, pharmacological and biological criteria. Our 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 several different brain receptors or proteins implicated in neuropsychiatric disorders e.g., cannabinoid (CB-1),serotonin (5-HT1A, 5-HT4), TSPO (formerly known as PBR), and glutamate (mGluR1,mGluR5)receptors, efflux transporters (P-gp) and protein deposits such as beta-amyloid. Research in some of these areas has already been successful, providing new radiotracers for CB-1, TSPO, mGluR5 and P-gp for brain imaging in human subjects in support of clinical research. This human research is conducted in collaborartion with the Imaging Section of the same Branch (Chief Dr. R.B. Innis) under Food and Drug Administration (FDA) oversight through 'exploratory' or full investigational new drug applications (expINDs or INDs). This Section also interacts seamlessly with the Imaging Section to evalaute potential radiotracers. Many candidate radiotracers were designed, prepared and evaluated in reaching our goals. Two radiotracers developed for TSPO imaging ((C-11)PBR28 and (F-18)FBR) appeared 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, epilepsy and neurodegeneration (Alzhemier'sdisease). Other institutions (e.g., Cambridge University, Pitsburgh University)are also begining to use these radiotracers to perform clinical studies. An interesting and unexpected finding is that healthy human subjects may have different forms of TSPO that interact differently with (C-11)PBR28. Possible reasons for this finding, and its implications for TSPO imaging in patients, are being investigated with collaborators. New less discriminatory TSPO radioligands may be required. 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) 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 also entered use elsewhere. Our mGluR radiotracer ((F-18)SP203) 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 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 pump (e.g., P-gp)function 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, for this purpose, which has now reached the level of study in human subjects. (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). A radiotracer for imaging P-gp density is sought in addition to our radiotracer of function. 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). Methodology underpinning our radiotracer development was also advanced in areas such as the development of new synthetic methods, new radiolabeling procedures, and the application of micro-reactors to the miniaturization of radiochemistry. Over the past year, we have combined the use of microfluidics with a new F-18 labeling strategy to great effect, thereby 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. 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.,(C-11)MNPA (functional D2 receptor imaging), (C-11)CUMI (5-HT1A receptor imaging), (C-11)AZ (5-HT1B receptor imaging), (C-11)rolipram (PDE4 enzyme imaging), 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）旨在利用正电子发射断层扫描（PET）作为一种用于研究神经精神疾病的放射性成像技术，例如抑郁症，成瘾，精神分裂症和阿尔茨海默氏病。 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).宠物对此目的具有独特的功能和敏感，只要它可以与适当的宠物放射性示踪剂的使用相结合。这些探针的化学发展是利用PET在神经精神研究中的全部潜力的关键，但也被广泛认为是一项高度挑战和苛刻的科学任务。 潜在的成像目标远远超过可用的探针范围。 我们的实验室，MIB的PET放射药科学部分，在发现宠物放射线训练方面进行了一致的努力。这个过程与发现的努力和风险有关，因为成功的探针必须满足难以满足的化学，药理和生物学标准。我们的实验室配备了现代设施，用于进行药用化学和自动放射化学，并发出正电子化学碳11（T1/2 = 20分钟）和氟-18（T1/2 = 110分钟）。支持该研究计划所需的两个短寿命的放射性同位素是由NIH临床中心的相邻环体组织每天生产的。 我们的科学计划目前着重于开发新型探针，以成像和量化与神经精神疾病有关的几种不同的大脑受体或蛋白质，例如大麻素（CB-1），5-ht1a，5-HT4），TSPO，TSPO，TSPO（以前已知为PBR）和Glutamate（Mglur1，Mglur1，Mglur1，Mglur1，Mglur1，Mglur5）蛋白质沉积物，例如β-淀粉样蛋白。其中一些领域的研究已经成功，为CB-1，TSPO，MGLUR5和P-GP提供了新的放射性示例，用于人类受试者的脑成像，以支持临床研究。这项人类研究是通过食品和药物管理局（FDA）通过“探索性”或全面研究的新型药物应用（增长或INDS）的副业（FDA）监督的同一分支（R.B. Innis博士）的成像部分进行的。本节还与成像部分无缝相互作用，以评估潜在的放射性示踪剂。在实现我们的目标时，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例（（C-11）PBR28和（F-18）FBR）似乎非常成功，并且开始针对神经系统损伤进行研究，以调查脑炎症状况，例如创伤性脑损伤，脑损伤，中风，癫痫和神经性疾病（Alzhemier'sdisese）。其他机构（例如剑桥大学，皮茨堡大学）也开始使用这些放射性示例进行临床研究。 一个有趣且出乎意料的发现是，健康的人类受试者可能具有不同形式的TSPO，与（C-11）PBR28相互作用不同。该发现的可能原因及其对患者的TSPO成像的影响，正在与合作者进行研究。可能需要新的较小的歧视性TSPO放射线。 CB-1受体是大脑作用的大脑部位。我们新的CB-1放射性示例（（C-11）MEPPEP，（F-18）FMPEP）有可能研究吸毒成瘾，包括酒精中毒和可卡因成瘾。这些探针也可能与其他疾病（例如肥胖症）的研究有关。 （C-11）MEPPEP也已在其他地方输入使用。我们的mglur radiotracer（（F-18）SP203）有望具有脆弱X综合征，成瘾，自闭症和精神分裂症的研究价值。这种PET放射性示意剂在加快药物发现方面具有额外的价值（例如，请参阅《精神化学图》的流行特征文章，有针对性的放射性肉体剂帮助药物制造商在化学和工程新闻中浏览PET的神经系统景观，于2008年9月8日发表，讨论了我们的MGLUR radiotiotiotiotracer和其他探针）。血脑屏障的药物外排泵（例如P-gp）功能的成像是我们实验室的最新领域，与神经精神疾病的药物开发有关。为此，我们已经开发了一种改进的放射性示踪剂（C-11）DLOP，现在已经达到了人类受试者的研究水平。 （C-11）DLOP具有评估排出泵在阿尔茨海默氏病和其他神经退行性疾病（例如帕金森氏病）中的作用的临床研究潜力。 除了我们的放射性功能外，还要寻找用于成像P-gp密度的放射性示例。 我们开发的一些放射性示踪剂可能对出现在大脑外部的疾病具有价值。因此，TSPO放射性示例可能是研究周围炎症的一般性（例如，如动脉粥样硬化中发生），以及用于研究癌症研究（尤其是多药耐药性）的P-gp radiotracer。 在新的合成方法的发展，新的放射性标记程序以及将微反应器应用于放射化学的小型化化学化化学方面，基于我们的放射性培训发展的方法也得到了进步。在过去的一年中，我们将微流体的使用与新的F-18标签策略相结合，从而扩大了可能产生的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意剂的应用至关重要。也已经开发和利用了基于与质谱（LC-MS）（LC-MS）（LC-MS）（LC-MS）的液相色谱法（LC-MS）的新分析方法。 需要此信息以充分了解PET实验的结果并得出有意义的输出度量，例如大脑受体浓度。已经引入了敏感的LC-MS，以测量放射性示意剂半衰期和特异性放射性，还用于测量静脉内给药后血液中放射性示意剂浓度的测量。 LC-MS的使用避免了测量快速分娩放射性的需要。 已经在国内和国际上与外部学术化学和药物化学实验室建立了生产性合作，并通过Cradas（合作研究与发展协议）和NIH基金会的生物标志物联盟与制药公司建立了合作。与宠物及其相关放射化学和放射性培训的其他中心的其他中心也存在生产性合作。 该实验室积极培训各个级别的新科学家。 In addition, we produce several established radiotracers for PET investigations in animal or human subjects e.g.,(C-11)MNPA (functional D2 receptor imaging), (C-11)CUMI (5-HT1A receptor imaging), (C-11)AZ (5-HT1B receptor imaging), (C-11)rolipram (PDE4 enzyme imaging), and (C-11)PK 11195（TSPO结合位点成像）。在人类受试者中使用此类放射性剂的生产符合（食品和药物管理）在探索性或全面研究新药应用（IND）下的FDA要求。 每个使用这些放射性示例之一的PET实验都需要同一天的放射性示例的放射性合成，因此放射性示意剂的产生是常规的活性。 每年大约进行400份作品。