Automated microfluidic production of high specific activity PET tracers to enable routine CNS imaging

自动微流体生产高比活性 PET 示踪剂，以实现常规 CNS 成像

• 批准号: 8870224
• 负责人: Robert Michael van Dam
• 金额: $ 23.1万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8870224
• 关键词: Alzheimer' s Disease; Animals; Anions; Automation; Biological; Biological Process; Biology; Body part; Brain; Brain imaging; Central Nervous System Diseases; Clinical; Cyclotrons; Data; Diagnostic; Disease; Dose; Drug Formulations; Ensure; Epilepsy; Equipment Safety; Flumazenil; Fluorides; Fluorine; Goals; Guidelines; Health; High Pressure Liquid Chromatography; Human; Human Resources; Image; Injection of therapeutic agent; Injection product; Intervention; Label; Liquid substance; Literature; Manuals; Methods; Microfluidics; Monitor; Mus; Neuraxis; Neurologic; Parkinson Disease; Patients; Performance; Phase; Physiology; Plant Resins; Positron-Emission Tomography; Preparation; Procedures; Process; Production; Protocols documentation; Radioactivity; Radiochemistry; Radiolabeled; Rattus; Reaction; Reporting; Research; Research Infrastructure; Safety; Saline; Scanning; Site; Solid; Source; Staging; System; Technology; Testing; Time; Tissues; Tracer; Training; Translating; Translational Research; Translations; Water; base; contrast imaging; cost; dicyanmethane; disease mechanisms study; evaporation; flexibility; follow-up; hazard; imaging modality; in vivo; molecular imaging; neuroimaging; novel diagnostics; novel therapeutics; pre-clinical research; prototype; public health relevance; quantitative imaging; radiochemical; radioligand; radiotracer; receptor; receptor density; research and development; response; systems research; targeted imaging; tool; uptake; user-friendly

 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 SA is needed to obtain good image contrast in brains of small animals to ensure that receptor occupancy remains at tracer levels (<5%) and that pharmacologic effects are avoided. The lack of wide availability of diverse radioligands with high SA remains the bottleneck in accelerating the translation of new radiotracers into brain imaging diagnostics or routine tools for the study of CNS disorders and treatments. Production of PET probes in general requires very expensive equipment, safety infrastructure, and highly-trained personnel. High SA production using conventional approaches increases costs and hazards even further as generally one must use very high amounts of radioactivity (>1 Ci) to start the synthesis. Performing the synthesis of [18F]Fallypride and [18F]FLT in microliter volumes in a microfluidic chip has been shown to routinely result in very high SA (20 Ci/µmol or above) using low starting radioactivity (~10-20 mCi). Based on follow-up studies conducted to understand and optimize this phenomenon, the overall goal of this proposal is to construct a robust, automated, and user-friendly system based on microfluidic synthesis that would enable production of very high SA neuroimaging tracers on-site (i.e., in the imaging center). In Aim 1, an automated approach for the concentration of [18F]fluoride into a fixed volume, and delivery into the microfluidic chip, is developed. This will enable a variety of sources (i.e. different volumes and concentrations) of [18F]fluoride to be connected to the microfluidic system. In Aim 2, the remainder of the automation to complete the synthesis protocol, including purification and formulation in saline for injection, is developed. Using [18F]Fallypride as an example, the system performance will be validated and compared to results of manual production. Finally, in Aim 3, microscale synthesis protocols for three additional example CNS tracers ([18F]FET, [18F]FDDNP, and [18F]FMZ) with be developed and optimized, to demonstrate the versatility of the automated system, and to study the effect of SA on imaging in mice and rats to create guidance for the selection of optimal SA for such studies in preclinical research. It is expected that the prototype synthesis system will be applicable to a wide range of tracers, and will be scalable to the production of clinical doses. This proposal will result in a fully-automated prototype system for routine high specific activity PET tracer production that will enable imaging centers to produce several high SA PET tracers on-demand, thereby accelerating their ability to develop and translate new diagnostics and therapies for CNS disorders.

 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SA以在小动物的脑中获得良好的图像对比度，以确保受体占有率保持在示踪剂水平（<5%）并且避免药理学效应。具有高SA的多种放射性配体的广泛可用性的缺乏仍然是加速将新的放射性示踪剂转化为脑成像诊断或用于研究CNS病症和治疗的常规工具的瓶颈。PET探头的生产通常需要非常昂贵的设备、安全基础设施和训练有素的人员。使用常规方法的高SA生产甚至进一步增加了成本和危险，因为通常必须使用非常高量的放射性（>1 Ci）来开始合成。在微流控芯片中以微升体积进行[18 F]Fallypride和[18 F]FLT的合成已显示使用低起始放射性（~10-20 mCi）常规产生非常高的SA（20 Ci/µmol或以上）。基于为理解和优化这种现象而进行的后续研究，该提案的总体目标是构建一种基于微流体合成的稳健的、自动化的和用户友好的系统，该系统将能够现场生产非常高SA的神经成像示踪剂（即，在成像中心）。在目标1中，开发了一种用于将[18F]氟化物浓缩到固定体积并递送到微流体芯片中的自动化方法。这将使[18F]氟化物的各种来源（即不同体积和浓度）能够连接到微流体系统。在目标2中，开发了完成合成方案的自动化的其余部分，包括纯化和注射用盐水配制。以[18F]Fallypride为例，将对系统性能进行确认，并与手动生产的结果进行比较。最后，在目标3中，开发并优化了三种额外的示例CNS示踪剂（[18 F]FET、[18 F]FDDNP和[18 F]FMZ）的微尺度合成方案，以证明自动化系统的多功能性，并研究SA对小鼠和大鼠成像的影响，从而为临床前研究中的此类研究选择最佳SA提供指导。预计原型合成系统将适用于广泛的示踪剂，并将可扩展到临床剂量的生产。该提案将产生一个用于常规高比活度PET示踪剂生产的全自动原型系统，使成像中心能够按需生产几种高SA PET示踪剂，从而加快其开发和转化CNS疾病新诊断和治疗的能力。