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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.

项目总结/文摘