Magnetic Droplet Microfluidics as a Platform for the Concentration of [¹⁸F]Fluoride and Radiosynthesis of Sulfonyl [¹⁸F]Fluoride

Abstract

The radioisotope 18F is often considered the best choice for positron emission tomography (PET) owing to its desirable chemical and radiochemical properties. However, nucleophilic 18F-fluorination of large, water-soluble biomolecules, based on C-F bond formation, has traditionally been difficult. Thus, several aqueous fluorination approaches that offer significant versatility in radiopharmaceutical synthesis with sensitive targeting vectors have been developed. Furthermore, because 18F decays rapidly, production of these 18F-labeled compounds requires an automated process to reduce production time, reduce radiation exposure, and minimize losses due to the transfer of reagents during tracer synthesis. Herein, we report the use of magnetic droplet microfluidics (MDM) as a means to concentrate [18F]fluoride from the cyclotron target solution, followed by the synthesis of an 18F-labeled compound on a microfluidic platform. Using this method, we have demonstrated 18F preconcentration in a small-volume droplet through the use of anion exchanging magnetic particles. By using MDM, the preconcentration step took approximately 5 min, and the [18F]fluoride solution was preconcentrated by 15-fold. After the preconcentration step, an 18F-labeling reaction was performed on the MDM platform using the S-F bond formation in aqueous conditions to produce an arylsulfonyl [18F]fluoride compound which can be used as a prosthetic group to label PET targeting ligands. The high radiochemical purity of 95±1% was comparable to the 96% previously reported using a conventional method. In addition, when MDM was used, the total synthesis time was improved to 15 min with lower reagent volumes (50-60 μL) used.

Multi-GBq production of the radiotracer [18F]fallypride in a droplet microreactor

“…However, the large scale reactions (required for producing clinical doses) use similar volumes as conventional systems, generally minimizing reagent savings. 9 Recently, several droplet-based platforms have been developed for the synthesis of PET tracers, based on electro-wetting on dielectric (EWOD), 2,[11][12][13] passive droplet transport, 14 magnetic bead actuation, 15 or surface-tension traps. 16 These technologies enable reaction volumes to be scaled down to the microliter range (and reagent masses to the 10s of microgram level).…”

“…A different strategy was used in the magnetic droplet platform. 15 Functionalized magnetic beads were incubated with an initial droplet of radioisotope solution (unspecic volume) to trap the [ 18 F]uoride on the beads, and the droplet was magnetically transported to a capillary where the liquid was removed via vacuum. The authors suggest that the process can be repeated multiple times and can process 1 mL of liquid in only 5 min; however, the trapping capacity of the beads was limited and could only efficiently sequester $100 MBq [$3 mCi] of activity.…”

Flexible Ferrofluids: Design and Applications

“…Magnetic microfluidics not only inherits systematic precise control over individual fluid and droplet of traditional microfluidics, but also is characterized by simple actuation strategy, flexible controllability, remote operation, as well as noninvasive manipulation ability . Thanks to these superior advantages, magnetic microfluidics is playing a vital role in biomolecule delivery, chemical reactions, bioseparation, polymerase chain reaction (PCR), and many other applications …”

18F-labelling innovations and their potential for clinical application

“…The usefulness of electrochemical methods for the concentration of [ 18 F]fluoride suitable for microfluidic devices was successfully demonstrated by nucleophilic 18 F-substitution of several radiotracers [80,218]. In a novel development [ 18 F]fluoride is captured on QMA-tagged magnetic particles in a solution and subsequently released by ion-exchange with a K2CO3 solution [219].…”