Accelerating the discovery and development of neurotracers via high-throughput radiochemistry

通过高通量放射化学加速神经示踪剂的发现和开发

基本信息

批准号：
10636867
负责人：
ARION Xenofon CHATZIIOANNOU
金额：
$ 66.3万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-10 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10636867
关键词：
Acceleration Aging Automation Biodistribution Biological Biological Assay Brain Chemicals Chemistry Clinical Collection Consumption Creativeness Decontamination Development Disease Disease Progression Dose Ensure Equipment Exclusion Exposure to Health Image In Situ In Vitro Individual Infrastructure Injections Investigation Isotopes Label Lead Liquid substance Manuals Measurement Methods Mole the mammal Pathway interactions Patients Performance Positron-Emission Tomography Preparation Process Production Property Radiation exposure Radio Radioactive Radioactivity Radiochemistry Radioisotopes Rapid screening Reaction Reagent Research Research Personnel Safety Sampling Sensory Receptors Site Speed Spottings System Technology Time Tissues Tracer Work base clinical imaging clinically relevant cost design experimental study high throughput technology human error imaging approach imaging study improved in vivo in vivo evaluation in vivo imaging innovation new technology novel novel therapeutics operation pre-clinical pre-clinical research preclinical imaging pressure prototype radiation detector radiochemical rapid technique receptor scale up screening targeted imaging tool

项目摘要

PROJECT SUMMARY/ABSTRACT The continuous discovery of new biological targets presents opportunities to dramatically improve our understanding of diseases and normal function and provides new avenues for treatment. In vivo imaging of these targets via positron-emission tomography (PET) is an especially powerful tool to understand the initiation and progression of disease and to aid in the development of novel therapeutics. The major benefits of PET are the very high sensitivity (enabling imaging of rare targets such as neuroreceptors without saturating them), and the ability to image deep tissues (which provides translatability from preclinical research to later clinical use). But the development of useful and validated tracers can take years or decades. A significant limiting factor is the complexity and cost of radiochemistry, and the difficulty in using current technologies to optimize synthesis conditions – a key step toward achieving reliable production with sufficient yield to support initial imaging studies. Slow throughput and high reagent and isotope consumption mean that optimization studies are very expensive and time-consuming, and thus such studies tend to be very limited and are unlikely to find globally optimal conditions. These limitations also create pressures in other aspects of new probe development, e.g., significant efforts are made to reduce the number of “hits” so only a very small number of compounds are labeled and studied via in vitro and ex vivo assays and in vivo imaging. However, this selection process is imperfect as it sometimes leads to the pursuit of dead-ends while it excludes promising candidates. To more rapidly leverage preclinical and clinical imaging of new biological targets, the radiochemistry field is in urgent need of new tools to improve the tracer discovery and development process. Our proposed solution is the development of high-throughput radiochemistry methods. Arrays of droplet reactions have recently been introduced as a way to rapidly perform dozens of reactions in parallel from a single batch of radioisotope, with total reagent consumption of those reactions similar to a single batch on a conventional system. Furthermore, the droplet reactions can readily be scaled to quantities for preclinical or even clinical imaging. These methods could be used to efficiently explore a vast reaction parameter space in a matter of days (instead of weeks to months), or they could be used to label dozens of candidate compounds in parallel to perform screening based on the most relevant metric: in vivo properties. While these reaction arrays, operated using manual pipetting, have revealed the benefits and potential of high-throughput radiochemistry, this new technology requires significant further development and automation to increase safety and speed, and reduce the chance for human error. We propose to (1) integrate in situ radiation detectors to quantify the radioactivity at various stages of each reaction, (2) integrate a method to automatically sample the reactions for analysis (radio-TLC or radio-UPLC), and (3) use high-throughput methods to optimize the synthesis of 5 neurotracers that currently have low yield, develop at least one novel tracer, and develop best practices for high-throughput optimization in radiochemistry.

项目概要/摘要新生物靶标的不断发现提供了显着改善我们的机会了解疾病和正常功能并为这些疾病的体内成像提供新的途径。通过正电子发射断层扫描 (PET) 来确定目标是一种特别强大的工具，可用于了解起始和 PET 的主要优点是：非常高的灵敏度（能够对神经感受器等罕见目标进行成像而不使其饱和），并且深层组织成像的能力（提供从临床前研究到后期临床使用的可转化性）。但开发有用且经过验证的示踪剂可能需要数年或数十年的时间，一个重要的限制因素是。放射化学的复杂性和成本，以及使用现有技术优化合成的困难条件——实现可靠生产和足够产量以支持初始成像研究的关键一步。通量慢以及试剂和同位素消耗高意味着优化研究非常昂贵并且耗时，因此此类研究往往非常有限，并且不太可能找到全局最优的这些限制也给新探针开发的其他方面带来了压力，例如，显着的。我们努力减少“命中”的数量，因此只有极少数化合物被标记和通过体外和离体测定以及体内成像进行研究然而，这种选择过程是不完善的。有时会导致追求死胡同，同时排除有前途的候选人。为了更多地利用新生物靶点的快速临床前和临床成像，放射化学领域正在迫切需要新的工具来改进示踪剂的发现和开发过程。我们提出的解决方案是。高通量放射化学方法的发展最近得到了发展。被引入作为一种从单批放射性同位素快速并行进行数十个反应的方法，这些反应的总试剂消耗量与传统系统上的单批次反应类似。液滴反应可以很容易地缩放到临床前甚至临床成像的数量。可用于在几天内（而不是几周）有效地探索巨大的反应参数空间月），或者它们可以用于并行标记数十种候选化合物以进行基于筛选的最相关的指标：体内特性，而这些反应阵列使用手动移液操作，揭示了高通量放射化学的好处和潜力，这项新技术需要显着的进一步开发和自动化，以提高安全性和速度，并减少人类的机会我们建议（1）集成原位辐射探测器来量化每个阶段的放射性。反应，(2) 集成一种自动对反应进行采样以进行分析的方法（无线电 TLC 或无线电 UPLC）， (3)利用高通量方法优化目前产量较低的5种神经示踪剂的合成，开发至少一种新型示踪剂，并最好地开发放射化学高通量优化的实践。