Optimization of microfluidic PET tracer synthesis with Cerenkov imaging

Abstract

Microfluidic technologies provide an attractive platform for the synthesis of radiolabeled compounds. Visualization of radioisotopes on chip is critical for synthesis optimization and technological development. With Cerenkov imaging, beta particle emitting isotopes can be localized with a sensitive CCD camera. In order for Cerenkov imaging to also serve as a quantitative tool, it is necessary to understand how material properties relevant to Cerenkov emission, namely, index of refraction and beta particle stopping power, affect Cerenkov light output. In this report, we investigate the fundamental physical characteristics of Cerenkov photon yield at different stages of [18F]FDG synthesis on the electrowetting on dielectric (EWOD) microfluidic platform. We also demonstrate how Cerenkov imaging has enabled synthesis optimization. Geant4, a Monte Carlo program applied extensively in high energy physics, is used to simulate Cerenkov photon yield from 18F beta particles traversing materials of interest during [18F]FDG synthesis on chip. Our simulations show that the majority (approximately two-thirds) of the 18F beta particle energy available to produce Cerenkov photons is deposited on the glass plates of the EWOD chip. This result suggests the possibility of using a single calibration factor to convert Cerenkov signal to radioactivity, independent of droplet composition. We validate our simulations with a controlled measurement examining varying ratios of [18O]H2O, dimethyl sulfoxide (DMSO), and acetonitrile (MeCN), and find a consistent calibration independent of solvent composition. However, the calibration factor may underestimate the radioactivity in actual synthesis due to discoloration of the droplet during certain steps of probe synthesis. In addition to the attractive quantitative potential of Cerenkov imaging, this imaging strategy provides indispensable qualitative data to guide synthesis optimization. We are able to use this imaging technique to optimize the mixing protocol as well as identify and correct for loss of radioactivity due to the migration of radioactive vapor outside of the EWOD heater, enabling an overall increase in the crude radiochemical yield from 50±3% (n=3) to 72±13% (n=5).

In Vivo Localization of 90Y and 177Lu Radioimmunoconjugates Using Cerenkov Luminescence Imaging in a Disseminated Murine Leukemia Model

“…We have shown that initial in vitro phantom studies produced results comparable to those previously reported by other groups (4–6, 10–12, 15, 29–32). Increases in measured radiance positively correlated with increases in the quantity of activity irrespective of the radionuclide measured ( 90 Y or 177 Lu; Fig.…”

Rapid, efficient, and economical synthesis of PET tracers in a droplet microreactor: application to O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET)

“…For radio-thin-layer chromatography (TLC) analysis, TLC plates (Baker-flex silica gel IB-F sheets 2.5 × 7.5 cm, J.T. Baker, Phillipsburg, NJ) were spotted with 1 μL samples of the crude intermediate, crude final product, or purified final product, and were developed in 80% v/v MeCN in H 2 O, and then scanned with a radio-TLC scanner (miniGita star, Raytest, Inc., Wilmington, NC, USA), or with a Cerenkov luminescence imaging system (Dooraghi et al 2013). Retention factors of the observed radioactive species were: 0.0 ([ 18 F]fluoride), 0.3 ([ 18 F]FET), and 0.8 (fluorinated intermediate).…”

“…Of the several different microfluidic approaches reported in the last decade (Elizarov 2009;Keng and van Dam 2015;Miller et al 2010;Pascali and Matesic 2016;Rensch et al 2013), microvolume reaction approaches offer the greatest potential for reagent and instrument reductions (Dooraghi et al 2013;Elizarov et al 2010;Iwata et al 2018;Keng et al 2016;Lebedev et al 2012;Wang et al 2017). A particular configuration we are exploring is performing reactions in microliter-sized droplets on simple Teflon-coated silicon microfluidic chips, which has advantages of simple operation, low-cost disposable chips, and a compact system size, which reduces the necessary shielding.…”

Automation and interfaces for chemistry and biochemistry in digital microfluidics

“…Detection of decay-products enables quantifi cation of radioisotopes and is useful in a variety of cellular assays or monitoring microfl uidic devices that process radioisotopes. Detecting Cerenkov emissions with a sensitive CCD camera, Dooraghi et al 93 (Fig. 11e,f).…”

“…However, ITO is expensive, and oft en requires an additional layer of metal for the traces and contact pads, due to its relatively high resistivity. Hu et al demonstrated that single-walled carbon nanotubes can be used as a somewhat cheaper, transparent alternative to ITO 93 . To simplify fabrication, a recent report has shown that it is possible to introduce "windows" into actuation electrodes made of opaque electrode materials such as metals 95 , enabling optical detection of droplets without transparent conductors.…”