Multistep Synthesis of a Radiolabeled Imaging Probe Using Integrated Microfluidics

Abstract

Microreactor technology has shown potential for optimizing synthetic efficiency, particularly in preparing sensitive compounds. We achieved the synthesis of an [ 18 F]fluoride-radiolabeled molecular imaging probe, 2-deoxy-2-[ 18 F]fluoro- d -glucose ([ 18 F]FDG), in an integrated microfluidic device. Five sequential processes—[ 18 F]fluoride concentration, water evaporation, radiofluorination, solvent exchange, and hydrolytic deprotection—proceeded with high radio-chemical yield and purity and with shorter synthesis time relative to conventional automated synthesis. Multiple doses of [ 18 F]FDG for positron emission tomography imaging studies in mice were prepared. These results, which constitute a proof of principle for automated multistep syntheses at the nanogram to microgram scale, could be generalized to a range of radiolabeled substrates.

Advantages of Radiochemistry in Microliter Volumes

“…One [15], our group demonstrated release into~12 μL volume [49], and Lebedev et al [17] and Bejot et al [50] demonstrated release into 44 μL volume. This approach can be integrated with microfluidics by using packed-tubing cartridges [15], functionalized porous polymer monoliths [51], packed microchannels [52], or resinfilled inserts [12].…”

“…Microvalves [19], Copyright © 2013 Elsevier, Inc.) (g) EWOD chip with reaction volume ranging from 2 to 17 μL were used to close the reactor during reaction steps, and the permeability of the PDMS enabled escape of vapor for solvent exchange processes. By scaling up the reactor volume to 5 μL, it was possible to produce mCi amounts of [ 18 F]-labeled tracers [15]. Unfortunately, due to adverse interaction of PDMS with [ 18 F]fluoride [16], radioactivity losses were high and reliability was low.…”

“…This approach can be integrated with microfluidics by using packed-tubing cartridges [15], functionalized porous polymer monoliths [51], packed microchannels [52], or resinfilled inserts [12]. Control of trapping and release processes requires the use of valves with small internal volumes to choose which solution is flowed into the cartridge inlet (i.e., [ 18 F]fluoride or eluent) and whether the cartridge outlet is direct to an [ 18 O]H 2 O collection reservoir or the microfluidic chip.…”

“…Fully automated synthesizers have been developed based on some of the earlier reports of batch microfluidic chips, complete with reagent delivery, radioisotope concentration, synthesis, and cartridge-based purification or interfacing with an HPLC system [15,17,50,56].…”

Floating electrode optoelectronic tweezers: Light-driven dielectrophoretic droplet manipulation in electrically insulating oil medium

“…[2][3][4][5][6] It has been shown that multiple droplets can be individually addressed in an open oil chamber using physically patterned electrodes, although complex wiring and interconnection issues arise for addressing numerically large droplet arrays. 9,10 To solve this problem, a microfluidic device integrating a high voltage complementary metal-oxide semiconductor driving circuit recently achieved active and parallel droplet control. However, this approach increases the fabrication cost of microfluidic devices, which are often preferred to be disposable.…”