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）是一种分子成像模式，它利用放射性标记的示踪分子来瞄准、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的受体密度较低（例如皮摩尔/克组织受体浓度），合成具有高比活度（SA）的 PET 放射性配体对于体内神经成像至关重要。特别是，需要非常高比活性的放射性配体（例如[F-18]Fallyprid）才能在小动物的大脑中获得良好的图像对比度而不引起任何药理作用。缺乏能够产生高 SA 的多种放射性配体的强大、易于使用的放射合成器仍然是加速将新放射性示踪剂转化为脑成像诊断或中枢神经系统疾病和治疗研究的常规工具的瓶颈。由于与传统装置相比具有许多内在优势，过去几年中用于放射合成的微流体平台得到了积极的发展。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，从而产生更高的比活度示踪剂。在初步实验中，发现 EWOD 微流控芯片上产生的 [F-18]FDG 的比活性显着高于传统设备上产生的 (25 倍)。在此结果的基础上，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[F-18]Fallypride（一种针对大脑中低丰度D2/D3R受体的重要示踪剂）的放射合成，并将其比活度与大规模生产进行比较，以将[F-18]FDG结果扩展到针对CNS的示踪剂。在目标 2 中，将系统地改变 EWOD 芯片的几何形状，以了解对氟 19 含量以及比活性影响最大的因素。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，将针对该新芯片优化[F-18]Fallypride合成，并将在小动物成像中研究[F-18]Fallypride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性 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 通过小动物 PET 分子成像，将新的诊断和疗法快速转化为临床实践。

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.