Abstract
BackgroundConventional 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.ProceduresThe 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.ResultsThe 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.ConclusionsA 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.
Highlights
Conventional scale production of small batches of Positron emission tomography (PET) tracers is an inefficient use of resources
Microscale [18F]FET synthesis optimization and automation To adapt the 2-step synthesis of [18F]FET from the macroscale to the microscale, the precursor and base quantities were initially scaled down nearly 300–490-fold from values reported in conventional synthesis (Bourdier et al 2011; Hamacher and Coenen 2002), i.e. to 75 nmol of TBAHCO3 (1 μL, 0.075 M) and 30 nmol of the TET precursor in 20 μL
During early syntheses the fluorination temperature was set at 80 °C, slightly lower than what has been reported in conventional syntheses (i.e., 85 °C (Hamacher and Coenen 2002) or 100 °C (Bourdier et al 2011)) to further mitigate evaporation, and the reaction time was set for 5 min
Summary
Conventional scale production of small batches of PET tracers (e.g. for preclinical imaging) is an inefficient use of resources. In which the chemistry is carried out in mL volume scales, relatively high reagent amounts (1 s to 10s of mg) are needed to achieve a sufficient concentration for good reaction yield in a short time, and for [18F]fluoride chemistry high amounts of radioactivity (10s of GBq) are needed to achieve high molar activity (Sergeev et al 2018a) These factors contribute to inefficient use of resources in the preparation of small batches of tracers, such as needed for preclinical imaging, or for a single clinical PET scan, where much of the prepared batch would be wasted. These advantages are especially relevant for smaller batch production of PET tracers, but can benefit the production of larger batches (Chao et al 2018b)
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