PET Radiopharmaceutical Sciences

PET 放射性药物科学

• 批准号: 8939964
• 负责人: Victor W Pike
• 金额: $ 446.31万
• 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/8939964
• 关键词: Academia; Affect; Alzheimer' s Disease; Animals; Anxiety; Area; Autistic Disorder; Behavior; Biochemical Process; Biological Markers; Biological Models; Blood; Blood - brain barrier anatomy; Brain; CNR1 gene; Cannabis; 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; Functional disorder; GRM1 gene; GRM5 gene; Genetic; Glutamates; Half-Life; Health Sciences; Human; Image; Imaging Techniques; Inflammatory; Institution; International; Investigation; Investigational New Drug Application; Japan; Label; Laboratories; Life; Logistics; Mass Spectrum Analysis; Measures; Mental Depression; Mental disorders; 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; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Physics; Positron; Positron-Emission Tomography; Production; Prostaglandin-Endoperoxide Synthase; Proteins; Psychiatry; Pump; Radio; Radioactive; Radioactivity; Radiochemistry; Radioisotopes; Radiolabeled; Radiopharmaceuticals; Reporting; Research; Risk; Schizophrenia; Science; Scientist; Sensory Receptors; Services; Stroke; Techniques; Therapeutic; Training; Traumatic Brain Injury; United States Food and Drug Administration; United States National Institutes of Health; Universities; Work; addiction; base; design; drug discovery; efflux pump; human subject; imaging modality; improved; insight; interest; intravenous administration; mild cognitive impairment; molecular imaging; molecular site; neuroinflammation; neuropsychiatry; novel; phosphodiesterase IV; programs; radiochemical; radiotracer; receptor; research study; response; 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 (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 radiotracers 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 (PRSS) 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, CB1 and glutamate (NMDA, mGlu1, mGlu5)receptors, COX and PDE enzymes,P-gp and BCRP 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, complicating 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 is now being 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 in human with others developed earlier. In collaboration with the Karolinska Institutet, this radiotracer was used to study occupancy of this receptor by experimental drugs. mGlu5 receptor radiotracers also have interest for the study of addiction, as well as other disorders, notably Fragile X, an autistic condition, and schizophrenia. We compared two new high-performing mGlu5 radiotracers(C-11SP203 and C-11FPEB)in human subjects in order to establish the best for more widespread application. We also developed a radiotracer (F-18FIMX) for a very related receptor target, namely mGlu1. Studies in human show this radiotracer to perform exceptionally well. NMDA is another protein acted upon by the important neurotransmitter, glutamate. We are continuing to assess the feasibility of imaging 'working' NMDA receptors, primarily because of their suspected importance in schizophrenia. Several new candidate radiotracers are being evaluated in animals. 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. Gottesman 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 collaborating with academia (Riken, Japan) to evaluate their early radiotracer for this target in human subjects. PET radiotracers can provide important quantitative information on experimental therapeutics 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 targeted at proteins that have not previously been imaged in living human brain, and that 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 experiments. 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-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 200 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）作为一种用于研究神经精神疾病的放射性成像技术，例如自闭症，抑郁症，成瘾，精神分裂症和阿尔茨海默氏病（AD）。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，以测量活着的人脑中低水平蛋白的变化，在这些蛋白质中，这些蛋白可能与神经精神疾病的发展有关。 这种蛋白质包括大脑内的神经感受器，酶和斑块，以及在血脑屏障上的药物外转运蛋白。当成功耦合使用有效的PET放射性示波器时，PET是一种独特的强大和敏感的成像方式。新生物化学特异性放射性示踪剂的化学发展是利用PET在神经精神研究中的全部潜力的关键。成功的宠物放射性示踪剂必须满足各种难以满足的标准，因此宠物放射性示踪剂的发展是一项艰巨的科学任务。 实际上，这项研究在必要的努力和风险方面与发现药物发现有一些相似之处 - 因为需要放射性示例满足如此广泛的标准。此外，潜在有趣的成像靶标（脑蛋白）的数量远远超过了可用且有用的放射性示例范围。 在MIB中，PET放射性药物科学部分（PRSS）对发现PET放射性示意剂的所有化学和放射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的成像部分（首席：R.B. Innis博士）无缝相互作用，以早日评估生物模型和动物中潜在的放射性示踪剂。随后的人类受试者的宠物研究还通过“探索性”或“完整”的新型药物应用与食品和药物管理局监督下的成像部分合作进行。 我们目前正在为多个目标开发宠物放射性示例。 其中包括TSPO，CB1和谷氨酸（NMDA，MGLU1，MGLU5）受体，COX和PDE酶，P-GP和BCRP外排转运蛋白和Tau原纤维沉积物。 我们为TSPO成像开发的一种放射性示例（C-11PBR28）正在应用于对各种神经系统损伤的响应（例如，中风，癫痫和神经变性）的响应。这种放射性示例似乎是从轻度认知障碍到成熟阿尔茨海默氏病（AD）过渡的生物标志物。现在，其他几个机构正在与C-11PBR28合作。 一个意外的发现是，健康的人类受试者由于遗传差异的微小差异，带有两种不同形式的TSPO中的一种或两个，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，我们试图开发遗传上不敏感的TSPO放射性示例。在这方面，一种新的放射性示踪剂C-11176似乎很有希望，现在正在人类受试者中进行评估。我们还开发了一种新的化学型，可以为TSPO提供优质的PET放射性示踪剂。此外，我们正在为与神经炎症研究有关的其他靶标开发放射性示例，例如环氧合酶（COX）酶。 大麻受体与成瘾研究有关。我们开发了一种新的CB1受体放射性示例C-11SD5024，并将其与其他人与其他人进行了比较。与Karolinska Institutet合作，该放射性示例用于研究通过实验药物对该受体的占用率。 MGLU5受体放射性示例也对成瘾研究以及其他疾病（尤其是脆弱的X，自闭症疾病和精神分裂症）都有兴趣。我们比较了人类受试者中两个新的高性能MGLU5辐射示例（C-11SP203和C-11FPEB），以便为更广泛的应用建立最好的。我们还开发了针对非常相关的受体靶标的radiotracer（F-18FIMX），即MGLU1。 人类的研究表明，这种放射性示踪剂表现出色。 NMDA是由重要的神经递质谷氨酸作用的另一种蛋白质。我们正在继续评估成像“工作” NMDA受体的可行性，这主要是因为它们在精神分裂症中的重要性。在动物中评估了几种新的候选放射性示例。 血脑屏障（BBB）处的药物外泵可能与AD这样的条件涉及。 P-GP和BCRP是BBB上两个最普遍的泵。 在我们成功地开发了C-11DLOP来研究P-gp功能之后，我们现在正在与DRS合作开发用于BCRP泵的互补放射性示踪剂。 M. Gottesman and M. Hall（NCI）。 C-11DLOP正在NIH和其他地方用于临床研究。 与Diaz-Arrastia教授及其同事（统一的卫生科学服务大学）合作，我们正在开发用于成像神经原纤维缠结（TAU蛋白）的放射性示例，这可能是神经退行性疾病的发展，例如AD和创伤性脑损伤。 我们还与学术界（日本Riken）合作评估了他们在人类受试者中为此目标的早期放射性示踪剂。 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，例如越过BBB并与靶蛋白互动的能力。在与学术界和制药公司的合作中，我们为此开发了几种放射性示踪剂。 这些放射性示例中的一些是针对以前从未在活人大脑中成像的蛋白质，并且可能最终具有临床研究实用性。 我们继续推进方法，以改善放射性示踪剂的发展。在几个领域取得了进展，包括合成，放射性映射方法以及使用微反应器进行放射化学研究。尤其是，我们将微流体的使用与新的标签策略相结合，以扩大我们候选F-18标记的放射性示踪剂的范围。引入了敏感的质谱法（LC-MS/MS），以测量放射性示意剂的半衰期和特定的放射性，并正在开发静脉内给药后血液中的放射性示意剂浓度，这是分析PET实验所必需的。 LC-MS/MS避免了与测量快速分期放射性相关的苛刻物流。 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，还通过合作研发协议以及NIH基金会的生物标志物财团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。 该实验室积极在研究生和博士后一级培训该领域的新科学家。 我们生产一些有用的放射性示例，这些放射性示例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）。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200种作品。