PET Radiopharmaceutical Sciences

PET 放射性药物科学

• 批准号: 8342130
• 负责人: Victor W Pike
• 金额: $ 333.01万
• 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/8342130
• 关键词: Alcoholism; Alzheimer' s Disease; Amyloid beta-Protein; Amyloid deposition; Animals; Anxiety; Application procedure; Area; Atherosclerosis; Autistic Disorder; Behavior; Biochemical; Biochemical Process; Biological; Biological Markers; Blood; Blood - brain barrier anatomy; Brain; Brain imaging; CNR1 gene; 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; Dose; Drug Addiction; Drug Efflux; Drug Receptors; Enzymes; Epilepsy; Evaluation; Fluorine; Foundations; Fragile X Syndrome; GRM1 gene; GRM5 gene; Generic Drugs; Glutamates; Half-Life; Histamine; Human; Image; Imaging Techniques; Inflammation; Inflammatory; Institution; International; Investigation; Investigational New Drug Application; Label; Laboratories; Life; Liquid Chromatography; Malignant Neoplasms; Mass Spectrum Analysis; Measurement; Measures; Mental Depression; Metabolism; Methodology; Methods; Microfluidics; Miniaturization; Mission; Modeling; Molecular; Multi-Drug Resistance; Names; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Neurotransmitter Receptor; Neurotransmitters; Obesity; Organic Chemistry; Organism; Output; Oxytocin; Parkinson Disease; Pharmaceutical Chemistry; Pharmacologic Substance; Pharmacology; Physics; Positron; Positron-Emission Tomography; Process; Production; Proteins; Radio; Radioactive; Radioactivity; Radiochemistry; Radioisotopes; Radiolabeled; Radiopharmaceuticals; Reporting; Research; Research Activity; Risk; Role; Schizophrenia; Science; Scientist; Sensory Receptors; Serotonin; Serotonin Receptor 5-HT1A; Site; Stream; Stroke; Techniques; Training; Traumatic Brain Injury; United States Food and Drug Administration; United States National Institutes of Health; Universities; Work; addiction; analytical method; base; density; design; drug development; drug discovery; efflux pump; human subject; imaging modality; improved; insight; interest; intravenous administration; molecular imaging; neuropsychiatry; nociceptin; novel; phosphodiesterase IV; programs; radiochemical; radioligand; radiotracer; receptor; research and development; research study; response

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 living animal or human brain (e.g., regional neuroreceptor densities, neurotransmitter synthesis, enzyme concentrations, regional metabolism, amyloid deposition, drug efflux from brain). PET is a uniquely powerful and sensitive imaging modality for such purposes when successfully coupled to appropriate PET radiotracers. The chemical development of new radiotracer types is the key to exploiting the full potential of PET in neuropsychiatric research. Such radiotracer development is widely recognized as being a highly challenging and demanding scientific task. In fact, potential interesting imaging targets far exceed the range of available and useful radiotracers. Within MIB, our laboratory, the PET Radiopharmaceutical Sciences Section, places a concerted effort on all medicinal chemistry and radiochemical aspects of PET radiotracer discovery. This research activity has some parallels with drug discovery in terms of required effort and risk, because successful PET probes must fulfill a difficult-to-satisfy range of chemical, pharmacological and biological criteria. In support of our mission,our laboratories are equipped with facilities for performing medicinal chemistry and automated radiochemistry with positron-emitting carbon-11 (t1/2 = 20 min) and fluorine-18 (t1/2 = 110 min). These two short-lived radioisotopes are available to us daily from the adjacent cyclotrons of the NIH Clinical Center (Chief Dr. P. Herscovitch). Our program currently focuses on developing novel probes for studying many different brain receptors or proteins that are implicated in neuropsychiatric disorders. Examples are cannabinoid (CB-1, CB-2), serotonin (5-HT1A, 5-HT4), TSPO (formerly known as PBR), nociceptin (NOP), histamine-H3, oxytocin and glutamate (mGlu1, mGlu5)receptors, efflux transporters (P-gp) and protein deposits such as beta-amyloid. Our Section interacts seamlessly with the Imaging Section of our Branch (Chief: Dr. R.B. Innis) for early evaluation of potential radiotracers in animals. Subsequent PET research in human subjects is also performed in collaboration with the Imaging Section under Food and Drug Administration (FDA) oversight through 'exploratory' or full investigational new drug applications (expINDs or INDs). Our research has been successful in providing a stream of new radiotracers for CB-1, TSPO, mGluR5, NOP and P-gp for brain imaging in human subjects in support of clinical research and drug development. Two radiotracers (C-11PBR28 and F-18FBR), developed successfully for TSPO imaging, 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 (Alzheimer's disease). Other institutions (e.g., Pitsburgh University) are also begining to use these radiotracers to perform clinical studies. An interesting and unexpected finding is that healthy human subjects can have one or both of two different forms of TSPO that interact differently with C-11PBR28. New less discriminatory TSPO radioligands would therefore be useful and are under development. CB-1 receptors are the protein sites in brain that are acted upon by cannabis. Our new CB-1 radiotracers (C-11MePPEP, F-18FMPEP) have potential for the study of drug addiction, including alcoholism and cocaine addiction, and other disorders, such as obesity. Indeed, a recent study from our Branch with 11CMePPEP reveals definite changes in brain CB1 receptors in response to cannabis use. The use of C-11MEPPEP is also being taken uup elsewhere. Our mGluR radiotracers (F-18SP203, C-11SP203) are expected to have value for the study of Fragile X syndrome, addiction, autism and schizophrenia. Such PET radiotracers can have additional value in expediting drug discovery, since potentially they may be used in drug-receptor occupancy (RO)studies to determine dosing regimes to be used in clincial trials. The imaging of drug efflux pump (e.g., P-gp) function at the blood-brain barrier is an area of interest in our laboratory with relevance to drug development for neuropsychiatric disorders. We have developed a much improved radiotracer, named C-11dLop, for this purpose. C-11dLop may have value 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. Radiotracers capable of measuring increased efflux transporter action are also being developed. 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. 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/MS has been introduced for the measurement of radiotracer half-life and specific radioactivity, and is also being investigated for the measurement of radiotracer concentration in blood following intravenous administration. The use of LC-MS/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 some useful radiotracers that have been devloped elsewhere for PET investigations in animal or human subjects e.g.,C-11CUMI (5-HT1A receptor imaging), C-11rolipram (PDE4 enzyme imaging). The production of such radiotacers for use in human subjects also complies with (Food and Drug Administration) FDA requirements under exploratory or full Investigational New Drug applications (INDs). Each PET experiment with any radiotracer 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 living animal or human brain (e.g., regional neuroreceptor densities, neurotransmitter synthesis, enzyme concentrations, regional metabolism, amyloid deposition, drug efflux from brain). PET成功地耦合到适当的PET放射性示例时，是一种独特的强大和敏感的成像方式。新的放射性示意剂类型的化学发展是利用PET在神经精神研究中的全部潜力的关键。这种放射性示踪剂的发展被广泛认为是一项高度挑战和苛刻的科学任务。 实际上，潜在的有趣成像靶标远远超过了可用和有用的放射性示例范围。 在MIB内，我们的实验室，PET放射性药物科学部分，对PET Radiotracer Discovery的所有药物化学和放射化学方面进行了一致的努力。这项研究活动与发现的努力和风险有关，因为成功的PET探针必须实现难以满足的化学，药理和生物学标准。为了支持我们的任务，我们的实验室配备了进行药物化学和自动放射化学的设施，并具有发射正电子的碳11（T1/2 = 20分钟）和氟-18（T1/2 = 110分钟）。 NIH临床中心（P. P. Herscovitch博士）每天都可以从我们每天提供这两个短暂的放射性同位素。 我们的计划目前致力于开发新的探针，以研究与神经精神疾病有关的许多不同的大脑受体或蛋白质。实例是大麻素（CB-1，CB-2），5-羟色胺（5-HT1A，5-HT4），TSPO（以前称为PBR），NociCeptin（NOP），组胺-H3，氧蛋白-H3，氧蛋白质和谷氨酸和谷氨酸（MGLU1，MGLU1，MGLU5）受体，Efflux Transporters（P-GP）和蛋白酶（PP-gp）和蛋白酶蛋白酶蛋白酶和蛋白酶。我们的部分与我们分支的成像部分（首席：R.B. Innis博士）无缝相互作用，以对动物的潜在放射性示踪剂进行早期评估。随后的人类受试者的宠物研究还通过“探索性”或全面的研究新药应用（增值或INDS）与食品和药物管理局（FDA）监督下的成像部分合作进行。 我们的研究已经成功地为CB-1，TSPO，MGLUR5，NOP和P-GP提供了新的放射性示例，用于人类受试者的大脑成像，以支持临床研究和药物开发。 为TSPO成像成功开发的两个放射性示例（C-11PBR28和F-18FBR）开始针对神经系统损伤进行研究，以研究脑炎症状况，例如，创伤性脑损伤，中风，癫痫，癫痫和神经变性（Alzheimer病）。其他机构（例如，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以具有与C-11PBR28不同相互作用的两种不同形式的TSPO中的一种或两个。 因此，新的较不歧视性的TSPO放射线将是有用的，并且正在开发中。 CB-1受体是大麻作用于大脑中的蛋白质位点。我们的新的CB-1放射性示例（C-11meppep，F-18FMPEP）具有研究吸毒成瘾的潜力，包括酒精中毒和可卡因成瘾以及其他疾病，例如肥胖。实际上，我们分支机构的最新研究以11cmeppep揭示了脑CB1受体的明确变化，以响应大麻使用。在其他地方也将使用C-11meppep的使用也被带走了。我们的mglur radiotracers（F-18SP203，C-11SP203）预计将对脆弱的X综合征，成瘾，自闭症和精神分裂症具有价值。这种PET放射性示踪剂在加快药物发现方面可能具有额外的价值，因为它们可能会用于药物受体占用（RO）研究以确定在层次试验中使用的剂量制度。 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感兴趣的领域，与神经精神疾病的药物开发有关。为此，我们开发了一种改进的Radiotracer，称为C-11DLOP。 C-11DLOP可能具有评估外排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）中的作用的价值。 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。也正在开发能够测量增加外排转运蛋白作用的放射性示例。 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。我们将微流体的使用与新的F-18标签策略相结合，从而效果很大，从而扩大了可能产生的标记为放射性示踪剂的候选F-18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/MS，以测量放射性的半衰期和特异性放射性，并正在研究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/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。 此外，我们产生了一些有用的放射性示例，这些放射性示例已在其他地方进行，用于在动物或人类受试者中进行宠物研究，例如C-11cumi（5-HT1A受体成像），C-11ROLIPRAM（PDE4酶成像）。在探索性或全面研究新药应用（IND）下，在人类受试者中使用此类放射性剂的生产也符合（食品和药物管理局）的需求。 每个使用任何放射性示例的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。