PET Radiopharmaceutical Sciences

PET 放射性药物科学

• 批准号: 8745705
• 负责人: Victor W Pike
• 金额: $ 434.13万
• 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/8745705
• 关键词: Academia; Alcohol abuse; Alzheimer' s Disease; Animals; Anxiety; Area; Autistic Disorder; Behavior; Biochemical Process; Biological Markers; Biological Models; Blood; Blood - brain barrier anatomy; Brain; CNR1 gene; Cannabinoids; Cannabis; Cannabis Abuse; Carbon; Chemicals; Chemistry; Clinical; Clinical Research; Collaborations; Cooperative Research and Development Agreement; Coupled; Cyclotrons; Dementia; Deposition; Development; Diagnosis; Disease; Drug Addiction; Drug Efflux; Enzymes; Epilepsy; Evaluation; Fluorine; Foundations; Fragile X Syndrome; GRM1 gene; GRM5 gene; Genetic; Glutamates; Half-Life; Health Sciences; Histamine; Human; Image; Imaging Techniques; Inflammatory; Institution; International; Investigation; Investigational New Drug Application; Japan; Label; Laboratories; Life; Logistics; Mass Spectrum Analysis; Measures; Mental Depression; Metabolism; Methodology; Methods; Microfluidics; Mission; Modeling; Molecular; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurologic; Neurotransmitter Receptor; Neurotransmitters; Organic Chemistry; Oxytocin; Pharmaceutical Chemistry; Pharmacologic Substance; Pharmacology; Physics; Positron; Positron-Emission Tomography; Production; Prostaglandin-Endoperoxide Synthase; Proteins; Pump; Radio; Radioactive; Radioactivity; Radiochemistry; Radioisotopes; Radiolabeled; Radiopharmaceuticals; Reporting; Research; Risk; Schizophrenia; Science; Scientist; Sensory Receptors; Serotonin Receptor 5-HT1A; Services; Site; Stroke; Techniques; Training; Traumatic Brain Injury; United States Food and Drug Administration; United States National Institutes of Health; Universities; Work; addiction; base; comparative; design; drug discovery; efflux pump; human subject; imaging modality; improved; insight; interest; intravenous administration; mild cognitive impairment; molecular imaging; neuroinflammation; neuropsychiatry; novel; phosphodiesterase IV; programs; radiochemical; radioligand; radiotracer; receptor; research study; response; tau Proteins

The Molecular Imaging Branch 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 (AD). 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 living human brain where these proteins may be involved in the progression of neuropsychiatric disorders. Such proteins include neuroreceptors, enzymes, and plaques within brain, and drug efflux transporters at the blood-brain barrier. PET is a uniquely powerful and sensitive imaging modality for such purposes when successfully coupled to the use of effective PET radiotracers. The chemical development of new biochemically specific radiotracers is the key to exploiting the full potential of PET in neuropsychiatric research. A successful PET radiotracer must satisfy a wide range of difficult-to-satisfy criteria and hence PET radiotracer development is a highly challenging scientific task. In fact, this research has some parallels with drug discovery in terms of required effort and risk - because of the need for radioligands to satisfy such a wide range of criteria. Moreover, the number of potentially interesting imaging targets (brain proteins) far exceeds the range of available and useful radiotracers. Within MIB, the PET Radiopharmaceutical Sciences Section places a concerted effort on all chemical and radiochemical 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 Imaging Section of our Branch (Chief: Dr. R.B. Innis) for early evaluation of potential radiotracers in biological models and 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. We are currently developing PET radiotracers for several targets. These include TSPO, cannabinoid (CB1), histamine, oxytocin, and glutamate (NMDA, mGlu1, mGlu5)receptors, COX and PDE enzymes,P-gp and BCR efflux transporters, and tau fibril deposits. One radiotracer that we have developed for TSPO imaging (C-11PBR28) is now being applied to investigate brain inflammatory conditions in response to various neurological insults (e.g., stroke, epilepsy and neurodegeneration). This radiotracer appears to be useful as a biomarker for the transition from mild cognitive impairment to full-blown Alzheimer's disease (AD). Several other institutions are now working with C-11PBR28. An unexpected finding is that healthy human subjects, because of small genetic differences, carry one or both of two distinct forms of TSPO and that these interact differently with C-11PBR28, complicatimg the analysis of PET studies. Consequently, we seek to develop genetically insensitive TSPO radiotracers. One new radiotracer, C-11ER176, appears promising in this regard and will be evaluated in human subjects. We are also developing a new chemotype that may provide superior PET radiotracers for TSPO. In addition, we are developing radiotracers for other targets relevant to the study of neuroinflammation, such as the cyclooxygenase (COX) enzymes. Cannabis receptors are relevant to the study of addiction. We developed a new CB1 receptor radiotracer C-11SD5024 and compared this with others developed earlier. One of these, F-18FMMEP, showed brain changes in CB1 receptors in cannabis and ethanol abuse. mGlu5 receptor radiotracers also have interest for the study of addiction, as well as other disorders, notably Fragile, an autistic condition, and schizophrenia. We produced two new mGlu5 radiotracers(C-11SP203 and C-11FPEB)for comparative evaluation in human subjects. We also developed a promising radiotracer (F-18FIMX) for a very related receptor target, namely mGlu1, which will be evaluated in human subjects. NMDA is another protein acted upon by the important neurotransmitter, glutamate. We are assessing the feasibility of imaging 'working' NMDA receptors, primarily because of their suspected imoportance in schizophrenia. Several candidate radiotracers are developed and are now being evaluated in animals for this purpose. Drug efflux pumps at the blood-brain barrier (BBB) may be involved in conditions such as AD. P-gp and BCRP are the two most prevalent pumps at the BBB. Following our successful development of C-11dLop to study P-gp function, we are now developing a complementary radiotracer for the BCRP pump in collaboration with Drs. M. Goettesman and M. Hall (NCI). C-11dlop is in use for clinical research at NIH and elsewhere. In collaboration with Prof. Diaz-Arrastia and colleagues (Uniformed Services University of the Health Sciences, we are developing radiotracers for imaging the accumulation of neurofibrillary tangles (tau protein), which may underlie the development of neurodegenerative disorders, such as AD and traumatic brain injury. We are also collaboring with academia (Riken, Japan) and Pharma (Avid, USA) to evaluate their early radiotracers for this target in human subjects. PET radiotracers can provide important quantitative information on experimental theraputics for neuropsychiatric disorders, such as ability to cross the BBB and to engage with a target protein. In collaborations with academia and Pharma, we developed several radiotracers for this purpose. Some of these radiotracers are targetted at proteins that have not previously been imaged in living human brain, and may have eventual clinical research utility. We continue to advance our methodology for improved radiotracer development. Progress was made across several areas, including synthesis, radiolabeling methods, and the use of micro-reactors for radiochemistry research. Especially, we combined the use of microfluidics with new labeling strategies to expand our range of candidate F-18 labeled radiotracers. Sensitive mass spectrometry (LC-MS/MS) was introduced to measure radiotracer half-life and specific radioactivity, and is also being developed to measure radiotracer concentration in blood following intravenous administration,as is required to analyze PET experiemnts. LC-MS/MS avoids the demanding logistics associated with measuring fast-decaying radioactivity. Productive collaborations were established with external academic chemistry and medicinal chemistry laboratories, nationally and internationally, and also with pharmaceutical companies through 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 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-11CUMI (for 5-HT1A receptor imaging), and C-11rolipram (for PDE4 enzyme imaging). 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 (AD)。这一使命的基础是开发新型放射性探针（放射性示踪剂），可与 PET 一起使用来测量活人大脑中低水平蛋白质的变化，其中这些蛋白质可能与神经精神疾病的进展有关。 这些蛋白质包括脑内的神经受体、酶和斑块，以及血脑屏障处的药物流出转运蛋白。当成功地与有效的 PET 放射性示踪剂的使用结合使用时，PET 是一种独特的强大且灵敏的成像方式，可用于此类目的。新型生化特异性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潜力的关键。成功的 PET 放射性示踪剂必须满足一系列难以满足的标准，因此 PET 放射性示踪剂的开发是一项极具挑战性的科学任务。 事实上，这项研究在所需的努力和风险方面与药物发现有一些相似之处——因为需要放射性配体来满足如此广泛的标准。此外，潜在有趣的成像目标（脑蛋白）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，PET 放射性药物科学部门在 PET 放射性示踪剂发现的所有化学和放射化学方面共同努力。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成像部门（负责人：R.B. Innis 博士）无缝互动，对生物模型和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 研究也是与成像部门合作在食品和药物管理局的监督下通过“探索性”或“全面”研究性新药申请进行的。 我们目前正在为多个目标开发 PET 放射性示踪剂。 这些包括 TSPO、大麻素 (CB1)、组胺、催产素和谷氨酸 (NMDA、mGlu1、mGlu5) 受体、COX 和 PDE 酶、P-gp 和 BCR 外排转运蛋白以及 tau 纤维沉积物。 我们开发的一种用于 TSPO 成像的放射性示踪剂 (C-11PBR28) 目前正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。这种放射性示踪剂似乎可用作从轻度认知障碍到全面阿尔茨海默病 (AD) 转变的生物标志物。其他几个机构现在正在与 C-11PBR28 合作。 一个意外的发现是，健康人类受试者由于微小的遗传差异，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。一种新的放射性示踪剂 C-11ER176 在这方面似乎很有前景，并将在人类受试者中进行评估。我们还在开发一种新的化学型，可以为 TSPO 提供优质的 PET 放射性示踪剂。此外，我们正在开发与神经炎症研究相关的其他靶点的放射性示踪剂，例如环氧合酶（COX）。 大麻受体与成瘾研究相关。我们开发了一种新的 CB1 受体放射性示踪剂 C-11SD5024，并将其与早期开发的其他放射性示踪剂进行了比较。 其中之一 F-18FMMEP 显示大麻和乙醇滥用时大脑中 CB1 受体的变化。 mGlu5 受体放射性示踪剂也对成瘾以及其他疾病的研究感兴趣，特别是脆弱症、自闭症和精神分裂症。我们生产了两种新的 mGlu5 放射性示踪剂（C-11SP203 和 C-11FPEB），用于人类受试者的比较评估。我们还针对非常相关的受体靶标（即 mGlu1）开发了一种有前景的放射性示踪剂 (F-18FIMX)，并将在人类受试者中进行评估。 NMDA 是另一种受重要神经递质谷氨酸作用的蛋白质。我们正在评估对“起作用的”NMDA 受体进行成像的可行性，主要是因为人们怀疑它们在精神分裂症中的重要性。为此目的，开发了几种候选放射性示踪剂，并正在动物身上进行评估。 血脑屏障 (BBB) 处的药物外排泵可能与 AD 等疾病有关。 P-gp 和 BCRP 是 BBB 中最常用的两种泵。 继我们成功开发 C-11dLop 以研究 P-gp 功能之后，我们现在正在与 Drs. 合作开发一种用于 BCRP 泵的补充放射性示踪剂。 M. Goettesman 和 M. Hall (NCI)。 C-11dlop 用于 NIH 和其他地方的临床研究。 我们与 Diaz-Arrastia 教授及其同事（健康科学制服服务大学）合作，正在开发放射性示踪剂，用于对神经原纤维缠结（tau 蛋白）的积累进行成像，这可能是 AD 和脑外伤等神经退行性疾病发展的基础我们还与学术界（日本理研）和制药公司（美国 Avid）合作，评估他们针对人类受试者这一目标的早期放射性示踪剂。 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，例如穿过血脑屏障和与目标蛋白结合的能力。为此，我们与学术界和制药公司合作开发了多种放射性示踪剂。 其中一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，并且可能具有最终的临床研究用途。 我们继续推进改进放射性示踪剂开发的方法。在多个领域取得了进展，包括合成、放射性标记方法以及微反应器在放射化学研究中的使用。特别是，我们将微流体的使用与新的标记策略相结合，扩大了候选 F-18 标记放射性示踪剂的范围。灵敏质谱 (LC-MS/MS) 被引入来测量放射性示踪剂半衰期和比放射性，并且还被开发用于测量静脉注射后血液中放射性示踪剂的浓度，这是分析 PET 实验所需的。 LC-MS/MS 避免了与测量快速衰变放射性相关的高要求物流。 我们与国内外的外部学术化学和药物化学实验室建立了富有成效的合作，并通过合作研究和开发协议以及美国国立卫生研究院基金会的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-11CUMI（用于 5-HT1A 受体成像）和 C-11rolipram（用于 PDE4 酶成像）。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。