PET Radiopharmaceutical Sciences

PET 放射性药物科学

• 批准号: 8556932
• 负责人: Victor W Pike
• 金额: $ 343.24万
• 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/8556932
• 关键词: Alcoholism; Alcohols; 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; Chemicals; Chemistry; Clinical; Clinical Research; Clinical Trials; 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; 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; 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; Relative (related person); 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; 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; single photon emission computed tomography; tau Proteins

The Molecular Imaging Branch (MIB) aims to exploit positron emission tomography (PET) as a radiotracer imaging technique for investigating neuropsychiatric disorders, such as autism, 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, 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, the number of potentially interesting imaging targets far exceeds 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 to perform 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). We are developing novel probes for studying many different brain proteins that are implicated in neuropsychiatric disorders. Examples are cannabinoid (CB-1), serotonin (5-HT1A, 5-HT4), TSPO (formerly known as PBR), nociceptin (NOP), histamine-H3, oxytocin and glutamate (mGlu1, mGlu5)receptors, efflux transporters (P-gp, BCRP) and protein deposits such as beta-amyloid and tau fibrils. 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 oversight through 'exploratory' or full investigational new drug applications (expINDs or INDs, respectively). Our research has provided a stream of new radiotracers for TSPO, CB-1, 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 being applied 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., Karolinska Institutet) have also taken up the use of these radiotracers. An interesting and unexpected finding is that healthy human subjects 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. One of these will soon be evaluated in hunan subjects. CB-1 receptors are the brain proteins acted upon by cannabis. Our new CB-1 radiotracers (11CMePPEP and F-18FMPEP) find application for the study of drug addiction, including cannabis use and alcoholism. Indeed, a recent study from our Branch with 11CMePPEP reveals definite changes in brain CB1 receptors in response to cannabis or alcohol. The use of C-11MEPPEP is also being taken up elsewhere. We are evaluating a further CB1 receptr radiotracer with PET in human subjects to assess its relative merits. Our research has also led to a radiotracers that is useful for studying CB1 receptors with an alternative imaging modality (SPECT). Our GluR5 radiotracers(F-18SP203, C-11SP203) are expected to have value for the study of Fragile X syndrome, other autism conditions, addiction, and schizophrenia. They may also expedite drug discovery for conditions such as Fragile X, since potentially they may be used in drug-receptor occupancy (RO) studies to determine dosing regimes to be used in clinical trials. The imaging of the function of the drug efflux pump (e.g., P-gp) 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 for other efflux pumps, such as BCRP are also sought, as are radiotracers capable of measuring increased efflux transporter action. Some of our radiotracers are likely to have value for diseases that present outside the brain. Thus, the TSPO radiotracers may have value 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 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 developed elsewhere for PET investigations in animal or human subjects e.g., C-11CUMI (5-HT1A receptor imaging), and 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 expINDS or 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. About 300 productions are performed annually

分子成像分支 (MIB) 旨在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，如自闭症、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，区域神经感受器密度、神经递质合成、酶浓度、淀粉样蛋白沉积、大脑中的药物流出）。当成功地与适当的 PET 放射性示踪剂结合时，PET 是一种独特的强大且灵敏的成像方式，可用于此类目的。新放射性示踪剂类型的化学开发是充分发挥 PET 在神经精神研究中潜力的关键。这种放射性示踪剂的开发被广泛认为是一项极具挑战性和高要求的科学任务。 事实上，潜在有趣的成像目标的数量远远超出了可用和有用的放射性示踪剂的范围。 在 MIB 内，我们的实验室 PET 放射性药物科学部致力于 PET 放射性示踪剂发现的所有药物化学和放射化学方面的工作。这项研究活动在所需的努力和风险方面与药物发现有一些相似之处，因为成功的 PET 探针必须满足一系列难以满足的化学、药理学和生物学标准。为了支持我们的使命，我们的实验室配备了能够使用正电子发射碳 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。我们每天都可以从 NIH 临床中心（首席 P. Herscovitch 博士）的相邻回旋加速器获得这两种短寿命放射性同位素。 我们正在开发新的探针来研究与神经精神疾病有关的许多不同的大脑蛋白质。例如大麻素 (CB-1)、血清素 (5-HT1A、5-HT4)、TSPO（以前称为 PBR）、伤害感受素 (NOP)、组胺-H3、催产素和谷氨酸 (mGlu1、mGlu5) 受体、外排转运蛋白 ( P-gp、BCRP）和蛋白质沉积物，例如 β-淀粉样蛋白和 tau 纤维。我们的部门与我们分部的成像部门（负责人：R.B. Innis 博士）无缝互动，以对动物中潜在的放射性示踪剂进行早期评估。随后的人类受试者 PET 研究也是在美国食品和药物管理局的监督下，通过“探索性”或全面研究性新药申请（分别为 expIND 或 IND）与影像科合作进行。 我们的研究为 TSPO、CB-1、mGluR5、NOP 和 P-gp 提供了一系列新的放射性示踪剂，用于人类受试者的脑成像，以支持临床研究和药物开发。 成功开发用于 TSPO 成像的两种放射性示踪剂（C-11PBR28 和 F-18FBR）正用于研究神经损伤引起的脑炎症状况，例如创伤性脑损伤、中风、癫痫和神经退行性疾病（阿尔茨海默病）。其他机构（例如卡罗林斯卡学院）也开始使用这些放射性示踪剂。 一个有趣且意想不到的发现是，健康人类受试者具有两种不同形式的 TSPO 中的一种或两种，它们与 C-11PBR28 的相互作用不同。 因此，新的歧视性较小的 TSPO 放射性配体将是有用的，并且正在开发中。其中一项很快将在湖南受试者中进行评估。 CB-1 受体是大麻作用的大脑蛋白质。我们的新型 CB-1 放射性示踪剂（11CMePPEP 和 F-18FMPEP）可用于药物成瘾研究，包括大麻使用和酗酒。 事实上，我们分支机构最近与 11CMePPEP 进行的一项研究揭示了大脑 CB1 受体对大麻或酒精的反应发生了明确的变化。 C-11MEPPEP 的使用也正在其他地方进行。我们正在人类受试者中使用 PET 进一步评估 CB1 受体放射性示踪剂，以评估其相对优点。我们的研究还开发出了一种放射性示踪剂，可用于通过替代成像方式 (SPECT) 研究 CB1 受体。我们的 GluR5 放射性示踪剂（F-18SP203、C-11SP203）预计对脆性 X 综合征、其他自闭症、成瘾和精神分裂症的研究具有价值。它们还可以加快针对脆性 X 等疾病的药物发现，因为它们有可能用于药物受体占用 (RO) 研究，以确定临床试验中使用的剂量方案。 血脑屏障处药物外排泵（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相关。为此，我们开发了一种经过大幅改进的放射性示踪剂，名为 C-11dLop。 C-11dLop 可能有助于评估外排泵在阿尔茨海默病和其他神经退行性疾病（例如帕金森病）中的作用。 除了我们的功能放射性示踪剂之外，我们还寻求一种用于 P-gp 密度成像的放射性示踪剂。还寻求用于其他外排泵（例如 BCRP）的放射性示踪剂，以及能够测量增加的外排转运蛋白作用的放射性示踪剂。 我们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 放射性示踪剂对于研究外周炎症（例如，动脉粥样硬化中发生的炎症）可能有价值，而 P-gp 放射性示踪剂对于研究癌症（尤其是多重耐药性）可能有价值。 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、新放射性标记程序以及微反应器在放射化学小型化中的应用等领域也取得了进步。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。 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/MS 已被引入用于测量放射性示踪剂半衰期和比放射性，并且还正在研究用于测量静脉注射后血液中放射性示踪剂的浓度。 使用 LC-MS/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，我们还生产一些已在其他地方开发用于动物或人类受试者 PET 研究的有用放射性示踪剂，例如 C-11CUMI（5-HT1A 受体成像）和 C-11rolipram（PDE4 酶成像）。用于人类受试者的此类放射性标记物的生产也符合（食品和药物管理局）FDA 根据 expINDS 或 IND 的要求。 使用任何放射性示踪剂的每次 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300部作品