Microliter radiosynthesizer for producing high specific activity PET ligands

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。尤其是放射性配基的比活度非常高(例如[F-18]在不引起任何药理作用的情况下，需要在小动物的大脑中获得良好的图像对比度。缺乏一种坚固、易用的放射性合成器，能够产生具有高SA的各种放射性配体，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。在过去的几年里，由于与传统装置相比具有许多固有的优点，用于放射合成的微流控平台得到了积极的追求。其中之一是操纵非常微小的体积(精确到亚微升)的能力。假设体积减小可以减少反应中的氟-19污染总量，从而产生更高的比活度示踪剂。在初步实验中，发现在EWOD微流控芯片上产生的[F-18]FDG的比活显著高于在常规仪器上产生的比活(25倍)。基于这一结果，在目标1中提出了一个制备高比活度示踪剂的新技术平台，将在EWOD芯片上开发针对大脑低丰度D2/D3R受体的重要示踪剂[F-18]FallyPride的放射合成，并将其比活性与大规模生产的比活性进行比较，将[F-18]FDG结果扩展到针对中枢神经系统的示踪剂。在目标2中，EWOD芯片的几何形状将被系统地改变，以了解对氟-19含量影响最大的因素，从而了解比活性。根据目标2的发现，目标3将开发一种优化的EWOD芯片，以生产高比活性的探针。随后，[F-18]FallyPride的合成将针对这一新芯片进行优化，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的结果将适用于大量其他示踪剂。这项提议将导致开发一种用于高比活性PET示踪剂生产的概念验证原型，该原型可能在更多 通过在小动物身上进行PET的分子成像，快速将新的诊断和治疗方法转化为临床实践。

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.