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Microliter radiosynthesizer for producing high specific activity PET ligands

用于生产高比活性 PET 配体的微升放射合成仪

基本信息

批准号：
8508266
负责人：
Robert Michael van Dam
金额：
$ 21.54万
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：
2012
资助国家：
美国
起止时间：
2012-07-15 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8508266
关键词：
Affect Affinity Animals Anions Area Binding Sites Biological Markers Biological Process Biology Body part Brain Brain Diseases Brain Neoplasms Brain imaging Central Nervous System Diseases Clinic Cyclotrons Development Devices Diagnostic Disease Dose Event Fluorides Fluorine Health Heating Human Image Ligands Liquid substance Methods Microfluidics Modeling Molecular Monitor Mus Necrosis Neuraxis Patients Physiology Positron-Emission Tomography Preparation Production Proteins Radiolabeled Rattus Reaction Reagent Relative (related person)Research Role Solvents Source Speed Staging Surface System Technology Thalamic structure Time Tissues Tracer Translating Translational Research Translations Work base clinical practice density design disease mechanisms study drug discovery empowered imaging modality improved in vivo instrument miniaturize molecular dynamics molecular imaging neuroimaging new technology novel novel diagnostics novel therapeutics prototype radioligand radiotracer receptor receptor density research and development research study response tool treatment response

项目摘要

DESCRIPTION (provided by applicant): Positron Emission Tomography (PET) is a molecular imaging modality that utilizes radiolabeled tracer molecules to target, image and quantify biological processes in vivo. PET tracers can be used to study disease mechanisms, to develop novel diagnostics and therapeutics, detect early stage disease, and monitor response to therapy. Due to low density of receptors in the CNS (e.g. picomole/gram tissue receptor concentration), it is critical to synthesize PET radioligands with high specific activity (SA) for n vivo neuroimaging. In particular, very high specific activity of radioligands (e.g. [F-18]Fallyprid) is needed to obtain good image contrast in brains of small animals without inducing any pharmacological effect. The lack of a robust, easy-to-use radiosynthesizer capable of the production of diverse radioligands with high SA remains the bottleneck in accelerating the translation of new radiotracers into brain imaging diagnostics or routine tools for study of CNS disorders and treatments. Microfluidic platforms for radiosynthesis have been actively pursued during the past several years due to a number of intrinsic advantages compared to conventional setups. One of these is the ability to manipulate very tiny volumes (down to the sub-microliter regime). It is hypothesized that volume reduction can reduce the total amount of fluorine-19 contamination in the reaction and thereby result in higher specific activity tracers. In preliminar experiments, the specific activity of [F-18]FDG produced on EWOD microfluidic chips was found to be significantly higher (25x) than that produced on conventional apparatus. Building upon this result, a new technology platform for the preparation of high specific activity tracers is proposed In Aim 1, the radiosynthesis of [F-18]Fallypride, an important tracer that targets low-abundance D2/D3R receptors in the brain will be developed on EWOD chips, and its specific activity compared to that of macroscale production, to extend the [F-18]FDG results to tracers targeting the CNS. In Aim 2, the geometry of the EWOD chip will be systematically varied to understand the factors that most strongly affect the fluorine-19 content and hence the specific activity. Based on the findings of Aim 2, an optimized EWOD chip will be developed in Aim 3 to produce high specific activity probes. Subsequently, [F-18]Fallypride synthesis will be optimized for this new chip and the effect of high and low specific activity of [F-18]Fallypride will be investigated n small animal imaging. It is expected that the results for [F-18]Fallypride will be generalizable toa large number of other tracers. This proposal will result in the development of a proof-of-concept prototype for high specific activity PET tracer production that could serve a critical role in more rapidly translating new diagnostics and therapies to clinical practice via molecular imaging with PET in small animals.

描述（由申请人提供）：正电子发射断层扫描（PET）是一种分子成像模式，其利用放射性标记的示踪分子来靶向、成像和量化体内生物过程。PET示踪剂可用于研究疾病机制，开发新的诊断和治疗方法，检测早期疾病，并监测对治疗的反应。由于CNS中受体的低密度（例如皮摩尔/克组织受体浓度），合成具有高比活性（SA）的PET放射性配体用于体内神经成像是至关重要的。特别地，需要非常高的放射性配体（例如[F-18]Fallyprid）的比活性以在小动物的脑中获得良好的图像对比度而不诱导任何药理学作用。缺乏一个强大的，易于使用的放射性合成器，能够生产不同的放射性配体与高SA仍然是瓶颈，在加速翻译新的放射性示踪剂到脑成像诊断或常规工具的研究中枢神经系统疾病和治疗。在过去的几年中，由于与常规装置相比具有许多固有的优点，用于放射合成的微流体平台已经被积极地追求。其中之一是能够操纵非常小的体积（低至亚微升范围）。据推测，体积减少可以减少反应中氟-19污染的总量，从而产生更高比活度的示踪剂。在EWOD微流控芯片上产生的[F-18]FDG的比活性比常规装置上产生的高出25倍。基于这一结果，提出了一种制备高比活度示踪剂的新技术平台。在目标1中，将在EWOD芯片上开发靶向脑中低丰度D2/D3 R受体的重要示踪剂[F-18]Fallypride的放射合成，并将其比活度与大规模生产的比活度进行比较，以将[F-18]FDG结果扩展到靶向CNS的示踪剂。在目标2中，将系统地改变EWOD芯片的几何形状，以了解最强烈地影响氟-19含量并因此影响比活度的因素。基于目标2的发现，目标3将开发优化的EWOD芯片，以产生高特异性活性探针。随后，[F-18]Fallypride的合成将针对这种新芯片进行优化，并将在小动物成像中研究[F-18]Fallypride的高和低比活性的影响。预计[F-18]Fallypride的结果将推广到大量其他示踪剂。该提案将导致开发用于高比活度PET示踪剂生产的概念验证原型，该原型可以在更多领域发挥关键作用。通过在小动物中使用PET进行分子成像，快速将新的诊断和治疗转化为临床实践。