Reports

Multistep Synthesis of a Radiolabeled Imaging Probe Using Integrated Microfluidics

Chung-Cheng Lee,^1* Guodong Sui,^3,4* Arkadij Elizarov,^2* Chengyi Jenny Shu,⁵ Young-Shik Shin,² Alek N. Dooley,⁶ Jiang Huang,⁸ Antoine Daridon,⁸ Paul Wyatt,⁸ David Stout,⁴ Hartmuth C. Kolb,^3,9 Owen N. Witte,^3,5,7 Nagichettiar Satyamurthy,³ James R. Heath,^2,3,4 Michael E. Phelps,^3,4 Stephen R. Quake,^1,10 Hsian-Rong Tseng^3,4

Microreactor technology has shown potential for optimizing synthetic efficiency, particularly in preparing sensitive compounds. We achieved the synthesis of an [¹⁸F]fluoride-radiolabeled molecular imaging probe, 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG), in an integrated microfluidic device. Five sequential processes—[¹⁸F]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 [¹⁸F]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.

¹ Department of Bioengineering, California Institute of Technology, Pasadena, CA 91125, USA.
² Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
³ Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA.
⁴ Crump Institute for Molecular Imaging, University of California, Los Angeles, CA 90095, USA.
⁵ Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095, USA.
⁶ UCLA Mass Spectrometry Facility, University of California, Los Angeles, CA 90095, USA.
⁷ Howard Hughes Medical Institute, University of California, Los Angeles, CA 90095, USA.
⁸ Fluidigm Corporation, 7100 Shoreline Court, South San Francisco, CA 94080, USA.
⁹ Molecular Imaging, Siemens Medical Solutions USA Inc., 6140 Bristol Parkway, Culver City, CA 90230, USA.
¹⁰ Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.

^* These authors contributed equally to this work.

To whom correspondence should be addressed. E-mail: quake{at}stanford.edu (S.R.Q.); hrtseng{at}mednet.ucla.edu (H.-R.T.)

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Free-Solution, Label-Free Molecular Interactions Studied by Back-Scattering Interferometry.

D. J. Bornhop, J. C. Latham, A. Kussrow, D. A. Markov, R. D. Jones, and H. S. Sorensen (2007)
Science 317, 1732-1736
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Blueprint for Imaging in Biomedical Research.

R. L. Ehman, W. R. Hendee, M. J. Welch, N. R. Dunnick, L. B. Bresolin, R. L. Arenson, S. Baum, H. Hricak, and J. H. Thrall (2007)
Radiology 244, 12-27
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In Vivo Quantitation of Glucose Metabolism in Mice Using Small-Animal PET and a Microfluidic Device.

H.-M. Wu, G. Sui, C.-C. Lee, M. L. Prins, W. Ladno, H.-D. Lin, A. S. Yu, M. E. Phelps, and S.-C. Huang (2007)
J. Nucl. Med. 48, 837-845
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Microfluidic Bubble Logic.

M. Prakash and N. Gershenfeld (2007)
Science 315, 832-835
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Microfluidic vias enable nested bioarrays and autoregulatory devices in Newtonian fluids.

E. P. Kartalov, C. Walker, C. R. Taylor, W. F. Anderson, and A. Scherer (2006)
PNAS 103, 12280-12284
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