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

 描述(申请人提供)：正电子发射断层扫描(PET)是一种分子成像方式，利用放射性标记的示踪分子来靶向、成像和量化体内的生物过程。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，并监测治疗反应。由于中枢神经系统中受体密度较低(如皮摩尔/克组织受体浓度)，合成高比活度(SA)的PET放射性配体对活体神经成像具有重要意义。特别是，需要非常高的SA才能在小动物的大脑中获得良好的图像对比度，以确保受体的占有率保持在示踪剂水平(&lt；5%)，并避免药物效应。缺乏广泛的具有高SA的各种放射性配基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中枢神经系统疾病和治疗的常规工具的瓶颈。生产PET探头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。使用传统方法的高SA产量甚至进一步增加了成本和危险，因为通常必须使用非常高的放射性(&gt；1Ci)来开始合成。在微流控芯片中进行微升容量的[18F]FallyPride和[18F]Flt的合成已被证明在使用低起始放射性(~10-20 mCI)的情况下通常会产生非常高的SA(20Ci/微摩尔或以上)。根据为了解和优化这一现象而进行的后续研究，这项提议的总体目标是构建一个基于微流控合成的强大、自动化和用户友好的系统，使现场(即成像中心)能够生产非常高SA的神经成像示踪剂。在目标1中，开发了一种将[18F]氟化物浓缩到固定体积并输送到微流控芯片中的自动化方法。这将使各种来源(即不同体积和浓度)的[18F]氟化物能够连接到微流控系统。在目标2中，开发了完成合成方案的其余自动化，包括提纯和注射用生理盐水配方。以[18F]FallyPride为例，对系统性能进行验证，并与手工生产的结果进行比较。最后，在目标3中，开发和优化了另外三个CNS示踪剂([18F]FET、[18F]FDDNP和[18F]FMZ)的微型合成方案，以展示自动化系统的通用性，并研究SA对小鼠和大鼠成像的影响，为临床前研究中此类研究选择最佳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。这项提议将产生一个用于常规高比活度PET示踪剂生产的全自动化原型系统，使成像中心能够按需生产几种高SA PET示踪剂，从而加快它们开发和转化针对中枢神经系统疾病的新诊断和治疗方法的能力。

 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.