PET Radiopharmaceutical Sciences

PET 放射性药物科学

• 批准号: 10266590
• 负责人: Victor W Pike
• 金额: $ 415.16万
• 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/10266590
• 关键词: Academia; Affect; Alzheimer' s Disease; Animals; Anti-Inflammatory Agents; Antidepressive Agents; Anxiety; Attention; Behavior; Binding Sites; Biochemical; Biochemical Process; Biological Models; Biology; Blood - brain barrier anatomy; Brain; Carbon; Chemicals; Chemistry; Clinical; Clinical Research; Collaborations; Coupled; Cyclotrons; Dementia; Development; Diagnosis; Disease; Drug Addiction; Enzymes; Epilepsy; Evaluation; Fluorine; Foundations; Fragile X Syndrome; Functional disorder; Genetic; Genotype; Glutamates; Human; Image; Imaging Techniques; In Vitro; Inflammatory; International; Investigation; Investigational New Drug Application; Investigational Therapies; Investigative Techniques; Ions; Label; Laboratories; Macrophage Colony-Stimulating Factor Receptor; Measures; Medicine; Mental Depression; Mental disorders; Metabolism; Methodology; Methods; Mission; Mitochondria; Modeling; Modernization; Molecular; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; National Institute of Mental Health; Nerve Degeneration; Neurologic; Neurotransmitter Receptor; New Agents; Organic Chemistry; Pathogenesis; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Physics; Positron; Positron-Emission Tomography; Production; Property; Prostaglandin-Endoperoxide Synthase; Proteins; Psychiatry; Radio; Radioactive; Radiochemistry; Radioisotopes; Radiolabeled; Radiopharmaceuticals; Reporting; Research; Rewards; Risk; Schizophrenia; Science; Scientist; Sensory Receptors; Serotonin; Serotonin Receptor 5-HT1B; Site; Specificity; Stroke; Techniques; Technology; Training; Traumatic Brain Injury; United States Food and Drug Administration; United States National Institutes of Health; Work; addiction; autism spectrum disorder; base; biomathematics; clinical center; cognitive function; cyclooxygenase 1; cyclooxygenase 2; design; designer receptors exclusively activated by designer drugs; drug discovery; experimental study; human subject; human tissue; hypocretin; improved; insight; interest; molecular imaging; molecular site; neuroimaging; neuroinflammation; neuropsychiatric disorder; neuropsychiatry; neurotransmission; nonhuman primate; novel; phosphodiesterase IV; phosphoric diester hydrolase; programs; radioligand; radiotracer; receptor; response; targeted imaging

Summary The Molecular Imaging Branch (MIB) aims to exploit positron emission tomography (PET) as an imaging technique for investigating neuropsychiatric disorders, such as autism, depression, addiction, schizophrenia, and Alzheimer's Disease. Fundamental to this mission is the development of novel radioactive probes (radiotracers) that can be used with PET to measure changes in low level proteins in the brains of living human subjects where these proteins are suspected to have critical involvement in the progression of neuropsychiatric disorders. Such proteins include some neuroreceptors, transporters, enzymes, and plaques. PET is uniquely powerful and sensitive when coupled with the use of biochemically-specific PET radiotracers. The chemical development of new radiotracers is the key to exploiting the full potential of PET in neuropsychiatric research. However, a successful PET radiotracer must satisfy a wide range of difficult-to-satisfy chemical, biochemical, and pharmacological criteria. Consequently, PET radiotracer development is highly challenging. In fact, our research has some parallels with drug discovery in that it entails high effort and heavy risk but can reap rich biomedical rewards. As of now, the number of potentially interesting PET imaging targets (brain proteins) far exceeds the range of currently available and useful radiotracers. Within MIB, the PET Radiopharmaceutical Sciences Section (PRSS) places a concerted effort on all chemical aspects of PET radiotracer discovery. Our laboratories are equipped for medicinal chemistry and automated radiochemistry with positron-emitting carbon-11 (t1/2 = 20 min) and fluorine-18 (t1/2 = 110 min). These two very short-lived radioisotopes are available to us daily from the adjacent cyclotrons of the NIH Clinical Center (Chief: Dr. P. Herscovitch). Our Section interacts seamlessly with the Section on PET Neuroimaging Sciences in our Branch (Chief: Dr. R.B. Innis) for early evaluation of candidate radiotracers in biological models and in animals. Subsequent PET research in humans is also performed in collaboration with the Imaging Section under Food and Drug Administration oversight through 'exploratory' or 'full' Investigational New Drug applications. All radiotracer production for PET studies in humans is now performed within the state-of-the-art NIH Clinical Center current good manufacturing practice (CGMP) laboratory. In the period covered by this report, we worked on developing and producing PET radiotracers for several protein targets. These include translocator protein 18 kDa (TSPO); the GluN2B sub-site of the NMDA receptor, serotonin subtype 1B (5-HT1B) receptors, orexin receptors, and certain enzymes (COX-1, COX-2, PDE1 and PDE4 subtypes, and OGA). One radiotracer that we earlier developed for TSPO imaging (C-11PBR28) has been applied by many imaging centers to investigate brain inflammatory conditions (i.e., neuroinflammation) in response to various neurological insults (e.g., stroke, epilepsy and neurodegeneration). An unexpected finding is that healthy human subjects, because of a genetic difference, carry either one or both of two distinct forms of TSPO and that these interact differently with C-11PBR28, complicating the analysis of PET studies. Consequently, we sought to develop genetically-insensitive TSPO radiotracers. We explored new chemotypes with potential to provide superior PET radiotracers for TSPO. One of our new radiotracers, C-11ER176, appeared promising for avoiding genotype sensitivity based on our evaluation in animals and in human tissue in vitro. In addition, while C-11ER176 does not show the expected genotype insensitivity in living humans, it does turn out to be one of the highest performing TSPO radiotracers yet known, and especially is able to quantify TSPO in all subjects of identified genotype. We are now producing this radiotracer for clinical studies in human subjects and other imaging centers plan to do so for this purpose. We are also developing longer-lived and therefore more broadly useful F-18 labeled versions of this radiotracer. Some of these already show high promise for continued development. We have been developing radiotracers for other targets relevant to the study of neuroinflammation, such as the cyclooxygenase (COX) subtype 1 and subtype 2 enzymes. Very promising C-11 labeled radiotracers have been identified. Two of these have been evaluated in human subjects and show imaging efficacy, They are now entering application in clinical studies. These radiotracers may provide more biochemical and cellular specificity for investigation of neuroinflammation. They can also prove useful for the development of improved anti-inflammatory drugs. We are working towards the development of radioligands with higher sensitivity for imaging COX-2, and also longer-lived (F-18 labeled) radioligands for both COX-1 and COX-2. We are also investigating radioligand development for imaging othe rtagetes of potential interest for the study of neuroinflammation, such as mitochondrial colony stimulating factor-1 receptor (mCSF1R). N-Methyl-D-aspartate (NMDA) receptors are proteins which are acted upon by glutamate for implementing normal brain function. Perturbations in NMDA function are strongly implicated in the pathogenesis of schizophrenia and other neuropsychiatric disorders, such as depression. Our research has led to promising radiotracers for imaging the GluN2B binding site on the NMDA receptor. We are evaluating these radiotracers for their imaging target selectivities. PET radiotracers can provide important quantitative information on experimental therapeutics for neuropsychiatric disorders, such as ability to cross the blood-brain-barrier and to engage with a target protein. In collaborations with academia and Pharma, we are developing several radiotracers for this purpose. These radiotracers are targeted at proteins that have not previously been imaged in living human brain that may have eventual clinical research utility. These proteins include, with clinical interest in parentheses, the enzyme OGA (dementia) and subtypes of phosphodiesterase (depression, cognitive function). Our radiotracer for imaging OGA has been found to perform excellently in human subjects. The development of radiotracers for phosphodiesterase subtypes has shown some promise. One radiotracer performed acceptably in non-human primate but less well in human. Alternatives with improved properties are now being developed. Our development of GluN2B radioligands has attracted attention and collaboration from Pharma for the possibility to develop new antidepressants. We are advancing methodology for improved radiotracer development. Thus, we recently developed new agents for radiolabeling, notably C-11fluoroform and F-18fluoroform. These expand chemical space for radiotracer development. We continue developing radiolabeling chemistries with these agents for preparing new radiotracers. For example, we have recently produced new TSPO radiotracers through these means. We have also developed C-11carbonyl difluoride as an entirely new and useful labeling agent. New methods for utilizing cyclotron-produced F-18fluoride ion and C-11carbon monoxide are being developed. The laboratory is active in training new scientists for this field at graduate and postdoctoral level. We produce some useful radiotracers that have been developed elsewhere for PET investigations in animal or human subjects e.g., C-11rolipram (for PDE4 enzyme imaging), and C-11-labeled radiotracers for investigation of DREADD technology. Each PET experiment requires a radiosynthesis of the radiotracer on the same day, and hence radiotracer production is a regular activity. .

概括 分子成像分支（MIB）旨在利用正电子发射断层扫描（PET）作为研究神经精神疾病的成像技术，例如自闭症，抑郁症，成瘾，精神分裂症和阿尔茨海默氏病。这项任务的基础是新型放射性探针（放射性示例）的发展，这些探针可与PET一起使用，以测量活着的人类受试者大脑中低水平蛋白的变化，在这些受试者中，这些蛋白质被怀疑对神经精神疾病的进展至关重要。这种蛋白质包括一些神经受体，转运蛋白，酶和斑块。 宠物与使用生化特异性的宠物放射性示例相结合时，具有独特的功能和敏感。新的放射性示例的化学发展是利用宠物在神经精神研究中的全部潜力的关键。但是，成功的宠物放射性示例必须满足各种难以满足的化学，生化和药理学标准。因此，宠物放射性示踪剂的发展极具挑战性。实际上，我们的研究与毒品发现有一些相似之处，因为它需要高昂的努力和巨大的风险，但可以获得丰富的生物医学奖励。截至目前，潜在有趣的PET成像靶标（脑蛋白）的数量远远超过了当前可用和有用的放射性示例的范围。 在MIB中，PET放射药科学部分（PRSS）在发现PET放射性示波器发现的所有化学方面进行了一致的努力。我们的实验室配备了具有发射正电子的碳11（T1/2 = 20分钟）和氟-18（T1/2 = 110分钟）的药物化学和自动放射化学。 NIH临床中心（首席：P。Herscovitch博士）每天都可以从我们每天提供这两个非常短的放射性同位素。我们的部分与我们分支机构中的PET神经影像学科学（首席：R.B. Innis博士）的部分无缝相互作用，以对生物模型和动物中的候选放射性示例进行早期评估。随后的人类宠物研究还通过“探索性”或“完整”的调查新药应用与食品和药物管理局监督下的成像部分合作进行。现在，在最先进的NIH临床中心当前良好的制造实践（CGMP）实验室中，所有用于人类宠物研究的放射性示例生产。 在本报告所涵盖的时期，我们致力于开发和生产几种蛋白质靶标的PET放射性示例。这些包括易位蛋白18 kDa（TSPO）； NMDA受体，5-羟色胺亚型1B（5-HT1B）受体，甲状腺素受体以及某些酶（COX-1，COX-1，COX-2，PDE1和PDE4亚型和OGA）的GLUN2B子位点。 我们先前为TSPO成像开发的一种放射性示例（C-11PBR28）已被许多成像中心应用于研究脑炎症条件（即神经炎症），以响应各种神经系统损伤（例如，卒中，癫痫，癫痫和神经脱发和神经化合物）。一个意外的发现是，健康的人类受试者由于遗传差异，带有两种不同形式的TSPO中的一种或两种，并且它们与C-11PBR28的相互作用不同，从而使对PET研究的分析变得复杂。因此，我们试图开发对遗传敏感的TSPO放射性示例。我们探索了新的化学型，具有为TSPO提供优质宠物放射性示例的潜力。我们的新放射性示例之一C-11176似乎是根据我们在动物和人类组织中的评估中避免基因型敏感性的有希望的。此外，虽然C-11176并未显示活于人类的预期基因型不敏感性，但事实证明，它确实是表现最高的TSPO放射性示例之一，尤其是能够在所有已识别基因型的受试者中量化TSPO。现在，我们正在为人类受试者和其他成像中心的临床研究生产这种放射性示例，计划为此目的这样做。我们还在开发寿命更长的寿命，因此具有更广泛的有用的F-18标记版本。其中一些已经对持续发展显示出很高的希望。 我们一直在开发与神经炎症研究有关的其他靶标的放射性示例，例如环氧酶（COX）亚型1和亚型2酶。已经确定了非常有前途的C-11标记的放射性示例。其中两个已在人类受试者中进行了评估，并显示出成像功效，现在正在临床研究中使用。这些放射性示例可能会提供更多的生化和细胞特异性，以研究神经炎症。它们还可以被证明可用于开发改善抗炎药。 我们正在努力开发对成像COX-2具有更高灵敏度的放射线，以及COX-1和COX-2的寿命更长（F-18标记）放射线。 我们还正在研究用于成像神经炎症研究的潜在兴趣的原始发展，例如线粒体菌落刺激因子-1受体（MCSF1R）。 N-甲基-D-天冬氨酸（NMDA）受体是蛋白质，由谷氨酸作用于实现正常脑功能的蛋白质。 NMDA功能的扰动与精神分裂症和其他神经精神疾病（如抑郁症）的发病机理非常重要。我们的研究导致了有望在NMDA受体上成像GLUN2B结合位点的有希望的放射性示例。我们正在评估这些放射性示例的成像目标选择性。 PET放射性示例可以提供有关神经精神疾病的实验疗法的重要定量信息，例如能够穿越血脑屏障并与靶蛋白互动的能力。在与学术界和制药公司的合作中，我们正在为此开发几种放射性示踪剂。 这些放射性示例针对以前从未在生命的人脑中成像的蛋白质，这些蛋白质可能最终具有临床研究实用性。这些蛋白质包括对括号的临床感兴趣，磷酸二酯酶的OGA（痴呆）和亚型（抑郁症，认知功能）。我们发现我们用于成像OGA的放射性示例在人类受试者中表现出色。磷酸二酯酶亚型的放射性示例的发展显示出一些希望。 一位放射性示意剂在非人类的灵长类动物中的表现可以接受，但在人类中的表现不太好。 现在正在开发具有改进特性的替代方案。 我们对Glun2B放射线的发展吸引了Pharma的关注和协作，以开发新的抗抑郁药。 我们正在推进改善放射性示踪剂发展的方法。因此，我们最近开发了用于放射性标记的新药物，尤其是C-11Fluoroform和F-18Fluoroform。 这些扩展了放射性示踪剂发育的化学空间。我们继续与这些药物一起制定放射性标记化学，以准备新的放射性示例。 例如，我们最近通过这些手段生产了新的TSPO放射性示例。我们还开发了C-11Carbonyl Difluoride作为一种全新的有用标签剂。利用环旋产生的F-18氟离子和C-11碳一氧化碳的新方法正在开发。 该实验室积极在研究生和博士后一级培训该领域的新科学家。 我们生产了一些有用的放射性示踪剂，这些放射性示踪剂是在其他地方开发的，用于在动物或人类受试者中进行宠物研究，例如C-11ROLIPRAM（用于PDE4酶成像）和C-11标记的放射性示例，以研究Dreadd Technology。每个PET实验都需要在同一天进行放射性示踪剂的放射性合成，因此放射性示踪剂的产生是常规的活性。 。