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) 作为一种成像技术来研究神经精神疾病，例如自闭症、抑郁症、成瘾症、精神分裂症和阿尔茨海默病。这一任务的基础是开发新型放射性探针（放射性示踪剂），可与 PET 一起使用来测量活体人类受试者大脑中低水平蛋白质的变化，这些蛋白质被怀疑与神经精神疾病的进展密切相关。这些蛋白质包括一些神经受体、转运蛋白、酶和斑块。 当与生化特异性 PET 放射性示踪剂结合使用时，PET 具有独特的强大和灵敏性。新型放射性示踪剂的化学开发是充分发挥 PET 在神经精神病学研究中的潜力的关键。然而，成功的 PET 放射性示踪剂必须满足一系列难以满足的化学、生化和药理学标准。因此，PET 放射性示踪剂的开发极具挑战性。事实上，我们的研究与药物发现有一些相似之处，因为它需要付出巨大的努力和巨大的风险，但可以获得丰富的生物医学回报。截至目前，潜在有趣的 PET 成像目标（脑蛋白）的数量远远超出了当前可用且有用的放射性示踪剂的范围。 在 MIB 内，PET 放射性药物科学部 (PRSS) 在 PET 放射性示踪剂发现的所有化学方面共同努力。我们的实验室配备了用于药物化学和自动放射化学的设备，包括正电子发射碳 11（t1/2 = 20 分钟）和氟 18（t1/2 = 110 分钟）。我们每天都可以从 NIH 临床中心（主任：P. Herscovitch 博士）的相邻回旋加速器获得这两种非常短寿命的放射性同位素。我们的部门与我们分部的 PET 神经影像科学部门（负责人：R.B. Innis 博士）无缝互动，以对生物模型和动物中的候选放射性示踪剂进行早期评估。随后的人体 PET 研究也是在食品和药物管理局的监督下，通过“探索性”或“全面”研究性新药申请与成像部门合作进行的。用于人体 PET 研究的所有放射性示踪剂生产现在均在最先进的 NIH 临床中心现行良好生产规范 (CGMP) 实验室内进行。 在本报告所述期间，我们致力于开发和生产针对多种蛋白质靶标的 PET 放射性示踪剂。其中包括易位蛋白 18 kDa (TSPO)； NMDA 受体、血清素亚型 1B (5-HT1B) 受体、食欲素受体和某些酶（COX-1、COX-2、PDE1 和 PDE4 亚型以及 OGA）的 GluN2B 亚位点。 我们早期为 TSPO 成像开发的一种放射性示踪剂 (C-11PBR28) 已被许多成像中心用于研究响应各种神经损伤（例如中风、癫痫和神经退行性变）的脑炎症状况（即神经炎症）。一个意外的发现是，由于遗传差异，健康人类受试者携带两种不同形式的 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 PET 研究的分析复杂化。因此，我们寻求开发遗传不敏感的 TSPO 放射性示踪剂。我们探索了新的化学型，有可能为 TSPO 提供优质的 PET 放射性示踪剂。根据我们对动物和人体组织的体外评估，我们的一种新型放射性示踪剂 C-11ER176 似乎有望避免基因型敏感性。此外，虽然 C-11ER176 在活体人类中没有表现出预期的基因型不敏感性，但它确实是迄今为止已知的性能最高的 TSPO 放射性示踪剂之一，特别是能够量化所有已识别基因型受试者的 TSPO。我们现在正在生产这种放射性示踪剂，用于人体临床研究，其他成像中心也计划为此目的这样做。我们还在开发这种放射性示踪剂的寿命更长、用途更广泛的 F-18 标记版本。其中一些已经显示出持续发展的良好前景。 我们一直在开发与神经炎症研究相关的其他靶标的放射性示踪剂，例如环氧合酶 (COX) 1 亚型和 2 亚型酶。非常有前途的 C-11 标记放射性示踪剂已经被发现。其中两种已经在人类受试者中进行了评估并显示出成像功效，它们现在正在进入临床研究应用。这些放射性示踪剂可以为神经炎症的研究提供更多的生化和细胞特异性。它们还可以用于开发改进的抗炎药物。 我们正在致力于开发对 COX-2 成像具有更高灵敏度的放射性配体，以及对 COX-1 和 COX-2 具有更长寿命（F-18 标记）的放射性配体。 我们还在研究放射性配体的开发，以对神经炎症研究中可能感兴趣的其他目标进行成像，例如线粒体集落刺激因子 1 受体 (mCSF1R)。 N-甲基-D-天冬氨酸 (NMDA) 受体是谷氨酸作用以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（例如抑郁症）的发病机制密切相关。我们的研究产生了有前景的放射性示踪剂，用于对 NMDA 受体上的 GluN2B 结合位点进行成像。我们正在评估这些放射性示踪剂的成像目标选择性。 PET 放射性示踪剂可以提供有关神经精神疾病实验治疗的重要定量信息，例如穿越血脑屏障和与目标蛋白结合的能力。为此，我们正在与学术界和制药公司合作开发多种放射性示踪剂。 这些放射性示踪剂针对的是以前未在活体人脑中成像的蛋白质，这些蛋白质可能具有最终的临床研究效用。这些蛋白质包括（括号内为临床意义）酶 OGA（痴呆）和磷酸二酯酶亚型（抑郁、认知功能）。我们的 OGA 成像放射性示踪剂被发现在人类受试者中表现出色。磷酸二酯酶亚型放射性示踪剂的开发已显示出一些希望。 一种放射性示踪剂在非人类灵长类动物中表现良好，但在人类中表现较差。 目前正在开发具有改进性能的替代品。 我们开发的 GluN2B 放射性配体引起了制药公司的关注和合作，以开发新的抗抑郁药。 我们正在推进改进放射性示踪剂开发的方法。因此，我们最近开发了用于放射性标记的新试剂，特别是 C-11 氟仿和 F-18 氟仿。 这些扩大了放射性示踪剂开发的化学空间。我们继续用这些试剂开发放射性标记化学物质，以制备新的放射性示踪剂。 例如，我们最近通过这些手段生产了新的TSPO放射性示踪剂。我们还开发了 C-11 二氟化碳作为一种全新且有用的标记剂。正在开发利用回旋加速器产生的 F-18 氟离子和 C-11 一氧化碳的新方法。 该实验室积极培养该领域的研究生和博士后新科学家。 我们生产一些有用的放射性示踪剂，这些放射性示踪剂已在其他地方开发用于动物或人类受试者的 PET 研究，例如 C-11rolipram（用于 PDE4 酶成像）和用于研究 DREADD 技术的 C-11 标记放射性示踪剂。每个 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。 。