Abstract
Microfluidic techniques are increasingly being used to synthesize positron-emitting radiopharmaceuticals. Several reports demonstrate higher incorporation yields, with shorter reaction times and reduced amounts of reagents compared with traditional vessel-based techniques. Microfluidic techniques, therefore, have tremendous potential for allowing rapid and cost-effective optimization of new radiotracers. This protocol describes the implementation of a suitable microfluidic process to optimize classical 18F radiofluorination reactions by rationalizing the time and reagents used. Reaction optimization varies depending on the systems used, and it typically involves 5–10 experimental days of up to 4 h of sample collection and analysis. In particular, the protocol allows optimization of the key fluidic parameters in the first tier of experiments: reaction temperature, residence time and reagent ratio. Other parameters, such as solvent, activating agent and precursor concentration need to be stated before the experimental runs. Once the optimal set of parameters is found, repeatability and scalability are also tested in the second tier of experiments. This protocol allows the standardization of a microfluidic methodology that could be applied in any radiochemistry laboratory, in order to enable rapid and efficient radiosynthesis of new and existing [18F]-radiotracers. Here we show how this method can be applied to the radiofluorination optimization of [18F]-MEL050, a melanoma tumor imaging agent. This approach, if integrated into a good manufacturing practice (GMP) framework, could result in the reduction of materials and the time required to bring new radiotracers toward preclinical and clinical applications.
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References
Miller, P.W., Long, N.J., Vilar, R. & Gee, A.D. Synthesis of 11C, 18F, 15O, and 13N radiolabels for positron emission tomography. Angew. Chem. Int. Ed. 47, 8998–9033 (2008).
Cai, L., Lu, S. & Pike, V. Chemistry with [18F]-fluoride ion. Eur. J. Org. Chem. 2008, 2853–2873 (2008).
Pascali, G., Watts, P. & Salvadori, P.A. Microfluidics in radiopharmaceutical chemistry. Nucl. Med. Biol. 40, 776–787 (2013).
Watts, P., Pascali, G. & Salvadori, P.A. Positron emission tomography radiosynthesis in microreactors. J. Flow Chem. 2, 37–42 (2012).
Rensch, C. et al. Microfluidics: a groundbreaking technology for PET tracer production? Molecules 18, 7930–7956 (2013).
Arima, V. et al. Radiochemistry on chip: towards dose-on-demand synthesis of PET radiopharmaceuticals. Lab Chip 13, 2328–2336 (2013).
Pascali, G., Mazzone, G., Saccomanni, G., Manera, C. & Salvadori, P.A. Microfluidic approach for fast labeling optimization and dose-on-demand implementation. Nucl. Med. Biol. 37, 547–555 (2010).
Ma, X., Tseng, W.-Y., Eddings, M., Keng, P.Y. & van Dam, R.M. A microreactor with phase-change microvalves for batch chemical synthesis at high temperatures and pressures. Lab Chip 14, 280–285 (2014).
Keng, P.Y. et al. Micro-chemical synthesis of molecular probes on an electronic microfluidic device. Proc. Natl. Acad. Sci. USA 109, 690–695 (2012).
Liang, S.H. et al. Rapid microfluidic flow hydrogenation for reduction or deprotection of 18F-labeled compounds. Chem. Commun. 49, 8755–8757 (2013).
Lebedev, A. et al. Batch-reactor microfluidic device: first human use of a microfluidically produced PET radiotracer. Lab Chip 13, 136–145 (2013).
Lapi, S.E. & Welch, M.J. A historical perspective on the specific activity of radiopharmaceuticals: what have we learned in the 35 years of the ISRC? Nucl. Med. Biol. 39, 601–608 (2012).
Krasikova, R. PET radiochemistry automation: state of the art and future trends in 18F-nucleophilic fluorination. Curr. Org. Chem. 17, 2097–2107 (2013).
Scott, P.J.H., Hockley, B.G. & Kilbourn, M.R. Radiochemical Syntheses, Radiopharmaceuticals for Positron Emission Tomography Vol. 1 (John Wiley & Sons, 2012).
Pascali, G. et al. Use of non-azeotropically dried complex in microfluidic radiofluorinations. J. Nucl. Med. Meeting Abstracts 53, 578 (2012).
Kim, H.W. et al. Rapid synthesis of [18F]FDG without an evaporation step using an ionic liquid. Appl. Radiat. Isot. 61, 1241–1246 (2004).
Aerts, J. et al. Fast production of highly concentrated reactive [18F] fluoride for aliphatic and aromatic nucleophilic radiolabelling. Tetrahedron Lett. 51, 64–66 (2010).
Wessmann, S.H., Henriksen, G. & Wester, H. Cryptate mediated nucleophilic 18F-fluorination without azeotropic drying. Nuklearmedizin. 51, 1–8 (2012).
Matesic, L. et al. Ascertaining the suitability of aryl sulfonyl fluorides for [18F]radiochemistry applications: a systematic investigation using microfluidics. J. Org. Chem. 78, 11262–11270 (2013).
Lu, S., Giamis, A.M. & Pike, V.W. Synthesis of [18F]fallypride in a micro-reactor: rapid optimization and multiple-production in small doses for micro-PET studies. Curr. Radiopharm. 2, 49–55 (2009).
Pascali, G., Nannavecchia, G., Pitzianti, S. & Salvadori, P.A. Dose-on-demand of diverse 18F-fluorocholine derivatives through a two-step microfluidic approach. Nucl. Med. Biol. 38, 637–644 (2011).
Graskemper, J.W., Wang, B., Qin, L., Neumann, K.D. & DiMagno, S.G. Unprecedented directing group ability of cyclophanes in arene fluorinations with diaryliodonium salts. Org. Lett. 13, 3158–3161 (2011).
Pascali, G., Kiesewetter, D.O., Salvadori, P.A. & Eckelman, W.C. Use of 1, 8-bis-(dimethylamino)-naphthalene/H18F complex as new radiofluorinating agent. J. Labelled Comp. Radiopharm. 47, 373–383 (2004).
Greguric, I. et al. Radiosynthesis of a novel PET fluoronicotinamide for melanoma rumour PET imaging; [18F]MEL050. Aust. J. Chem. 64, 873–879 (2011).
Bouvet, V., Wuest, M., Tam, P.H., Wang, M. & Wuest, F. Microfluidic technology: an economical and versatile approach for the synthesis of O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET). Bioorg. Med. Chem. Lett. 22, 2291–2295 (2012).
Ungersboeck, J. et al. Radiolabeling of [18F]altanserin: a microfluidic approach. Nucl. Med. Biol. 39, 1087–1092 (2012).
Dahl, K., Schou, M. & Halldin, C. Radiofluorination and reductive amination using a microfluidic device. J. Labelled Comp. Radiopharm. 55, 455–459 (2012).
Acknowledgements
We thank R. Manning and N. Paneras from Australian Nuclear Science and Technology Organisation (ANSTO) LifeSciences for the cyclotron production of [18F]-fluoride, and A. Kallinen from University of Helsinki for help in testing the protocol and data collection.
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G.P., L.M. and N.W. wrote the manuscript; T.L.C., B.H.F. and T.Q.P. reviewed the manuscript and tested the protocol; and P.A.S. and I.G. supervised the research.
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T.L.C. is an employee of Advion, Inc. The remaining authors declare no competing financial interests.
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Pascali, G., Matesic, L., Collier, T. et al. Optimization of nucleophilic 18F radiofluorinations using a microfluidic reaction approach. Nat Protoc 9, 2017–2029 (2014). https://doi.org/10.1038/nprot.2014.137
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DOI: https://doi.org/10.1038/nprot.2014.137
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