Conventional scale production of small batches of PET tracers (e.g. for preclinical imaging) is an inefficient use of resources. Using O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET), we demonstrate that simple microvolume radiosynthesis techniques can improve the efficiency of production by consuming tiny amounts of precursor, and maintaining high molar activity of the tracers even with low starting activity. The synthesis was carried out in microvolume droplets manipulated on a disposable patterned silicon “chip” affixed to a heater. A droplet of [18F]fluoride containing TBAHCO3 was first deposited onto a chip and dried at 100 °C. Subsequently, a droplet containing 60 nmol of precursor was added to the chip and the fluorination reaction was performed at 90 °C for 5 min. Removal of protecting groups was accomplished with a droplet of HCl heated at 90 °C for 3 min. Finally, the crude product was collected in a methanol-water mixture, purified via analytical-scale radio-HPLC and formulated in saline. As a demonstration, using [18F]FET produced on the chip, we prepared aliquots with different molar activities to explore the impact on preclinical PET imaging of tumor-bearing mice. The microdroplet synthesis exhibited an overall decay-corrected radiochemical yield of 55 ± 7% (n = 4) after purification and formulation. When automated, the synthesis could be completed in 35 min. Starting with < 370 MBq of activity, ~ 150 MBq of [18F]FET could be produced, sufficient for multiple in vivo experiments, with high molar activities (48–119 GBq/μmol). The demonstration imaging study revealed the uptake of [18F]FET in subcutaneous tumors, but no significant differences in tumor uptake as a result of molar activity differences (ranging 0.37–48 GBq/μmol) were observed. A microdroplet synthesis of [18F]FET was developed demonstrating low reagent consumption, high yield, and high molar activity. The approach can be expanded to tracers other than [18F]FET, and adapted to produce higher quantities of the tracer sufficient for clinical PET imaging.

中文翻译：

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在液滴微反应器中快速、高效、经济地合成 PET 示踪剂：应用于 O-(2-[18F]氟乙基)-L-酪氨酸 ([18F]FET)。


小批量 PET 示踪剂（例如用于临床前成像）的常规规模生产对资源的利用效率低下。使用O-(2-[18F]氟乙基)-L-酪氨酸([18F]FET)，我们证明简单的微体积放射合成技术可以通过消耗微量的前体并保持示踪剂的高摩尔活性来提高生产效率即使起始活动较低。合成是在固定在加热器上的一次性图案硅“芯片”上操纵微体积液滴进行的。首先将含有 TBAHCO3 的 [18F]氟化物液滴沉积到芯片上并在 100 °C 下干燥。随后，将含有60 nmol前体的液滴添加到芯片中，并在90℃下进行氟化反应5分钟。使用 HCl 滴在 90 °C 下加热 3 分钟即可去除保护基团。最后，将粗产物收集在甲醇-水混合物中，通过分析级放射性HPLC纯化并配制在盐水中。作为演示，我们使用芯片上生产的[18F]FET，制备了具有不同摩尔活性的等分试样，以探索其对荷瘤小鼠临床前PET成像的影响。纯化和配制后，微滴合成的总体衰变校正放射化学产率为 55 ± 7% (n = 4)。如果实现自动化，合成可在 35 分钟内完成。从 < 370 MBq 的活性开始，可以生产约 150 MBq 的 [18F]FET，足以进行多个体内实验，具有高摩尔活性 (48–119 GBq/μmol)。示范成像研究揭示了皮下肿瘤中[18F]FET的摄取，但由于摩尔活性差异（范围为0.37-48 GBq/μmol）而没有观察到肿瘤摄取的显着差异。 开发了 [18F]FET 的微滴合成方法，展示了低试剂消耗、高产率和高摩尔活性。该方法可以扩展到 [18F]FET 以外的示踪剂，并适用于产生足够用于临床 PET 成像的更高数量的示踪剂。