Microliter radiosynthesizer for producing high specific activity PET ligands

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，并监测对治疗的反应。由于中枢神经系统中受体密度低（如皮摩尔/克组织受体浓度），合成具有高比活性（SA）的PET放射配体对于体内神经成像至关重要。特别是需要非常高的放射性配体（如[F-18]Fallyprid）的比活性，才能在小动物大脑中获得良好的图像对比度，而不会产生任何药理作用。缺乏一个强大的，易于使用的放射性合成器，能够生产多种具有高SA的放射性配体，这仍然是加速将新的放射性示踪剂转化为脑成像诊断或常规工具以研究中枢神经系统疾病和治疗的瓶颈。在过去的几年中，由于与传统装置相比具有许多内在优势，放射性合成的微流控平台一直在积极追求。其中之一是能够操纵非常小的体积（小到亚微升）。假设体积减小可以减少反应中氟-19污染的总量，从而产生更高的比活性示踪剂。初步实验发现，在EWOD微流控芯片上制备的[F-18]FDG比活度明显高于在常规装置上制备的[F-18]FDG比活度（25倍）。在此基础上，本文提出了一个制备高比活性示踪剂的新技术平台。在第1项研究中，将在EWOD芯片上开发针对大脑中低丰度D2/D3R受体的重要示踪剂[F-18]Fallypride的放射性合成，并将其与宏观生产的比活性进行比较，将[F-18]FDG的结果扩展到针对中枢神经系统的示踪剂。在目标2中，将系统地改变EWOD芯片的几何形状，以了解最强烈影响氟-19含量的因素，从而了解比活性。基于Aim 2的研究结果，Aim 3将开发优化的EWOD芯片，以生产高比活性探针。随后，将针对该新型芯片对[F-18]Fallypride合成进行优化，并在小动物成像中考察[F-18]Fallypride高低比活性的影响。预计对[F-18]Fallypride的结果将推广到大量其他示踪剂。该提案将导致高比活性PET示踪剂生产的概念验证原型的开发，可以在更多的领域发挥关键作用

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.