Microfluidics: A Groundbreaking Technology for PET Tracer Production?
Abstract
:1. Introduction
2. PET Tracer Supply Chain and Synthesis Workflow
2.1. PET Tracer Production Workflow
2.2. PET Tracer Synthesis Process
2.3. Continuous-Flow & Batch Microfluidics
2.4. Capillary-Based, Hybrid and Integrated Lab-on-Chip Systems
2.5. Reusable and Disposable Fluid Paths
3. Functional Elements
3.1. Materials and Manufacturability
COC Cyclic Olefin Co-Polymer | pDCPD Polydicyclopentadiene | PEEK Polyether ether ketone | |
---|---|---|---|
Manufacturing method (single layer) | Injection molding 1) | Reaction injection molding 2) | Injection molding 7) |
Molding cycle time (approximated) | <1 min 1) | >5 min 2) | <1 min 7) |
Compatibility to acids | Good 1) | Medium 3) [53] | Good 8) |
Compatibility to bases | Good 1) | Good 3) | Good 8) |
Compatibility to alcohols | Good 1) | Good 3) | Good 9) |
Compatibility to acetonitrile | Good 1) | Good [53] | Good 10) |
Compatibility to DMSO | Good 1) | Good 4) | Good 10) |
Temperature Capability | 150 °C 1) | 140 °C 5) | 134 °C 5) |
Raw material cost (in US ¢ per gram) | ~1.2 ¢/g1) | ~1.3 ¢/g6) | ~26.1 ¢/g 5) |
3.2. Radiation Shielding
3.3. Fluid Transport and Control
3.4. Reagent Storage & Release
3.5. Macro-to-Micro Interface
3.6. Mixers, Reactors and Temperature Control
3.7. Phase Transfer and Activity Concentration
3.8. Intermediate and Final Purification
4. PET Tracer Production Workflow Optimization
4.1. Cyclotron to Quality Control Hardware Miniaturization
4.2. Evolution of Microfluidic Synthesizers for PET Tracer Production
5. Market Drivers for Next Generation PET Radiochemistry Platforms
6. Conclusions
Acknowledgments
Conflicts of Interest
References
- Phelps, M.E. Positron emission tomography provides molecular imaging of biological processes. PNAS 2000, 97, 9226–9233. [Google Scholar] [CrossRef]
- Audrain, H. Positron emission tomography (PET) and microfluidic devices: a breakthrough on the microscale? Angew. Chem. Int. Ed. Engl. 2007, 46, 1772–1775. [Google Scholar] [CrossRef]
- Lu, S.Y.; Pike, V.W. Micro-reactors for PET Tracer Labeling. In PET Chemistry: The Driving Force in Molecular Imaging; Schubiger, P.A., Lehmann, L., Friebe, M., Eds.; Springer Verlag: Berlin, Germany, 2006; pp. 271–289. [Google Scholar]
- Fortt, R.; Gee, A. Microfluidics: a golden opportunity for positron emission tomography? Future Med. Chem. 2013, 5, 241–244. [Google Scholar] [CrossRef]
- Miller, P.W. Radiolabelling with short-lived PET (positron emission tomography) isotopes using microfluidic reactors. J. Chem. Technol. Biotechnol. 2009, 84, 309–315. [Google Scholar] [CrossRef]
- Miller, P.W.; deMello, A.J.; Gee, A.D. Application of microfluidics to the ultra-rapid preparation of fluorine-18 labelled compounds. Curr. Radiopharm. 2010, 3, 254–262. [Google Scholar] [CrossRef]
- Lucignani, G. Pivotal role of nanotechnologies and biotechnologies for molecular imaging and therapy. Eur. J. Nucl. Med. Mol. Imaging 2006, 33, 849–851. [Google Scholar] [CrossRef]
- Shen, C.K.-F. Microfluidic-assisted radiochemistry and PET probe synthesis. MI Gateway 2011, 5, 1–5. [Google Scholar]
- Briard, E.; Zoghbi, S.S.; Siméon, F.G.; Imaizumi, M.; Gourley, J.P.; Shetty, H.U.; Lu, S.; Fujita, M.; Innis, R.B.; Pike, V.W. Single-step High-yield Radiosynthesis and Evaluation of a Sensitive 18F-Labeled Ligand for Imaging Brain Peripheral Benzodiazepine Receptors with PET. J. Med. Chem. 2009, 52, 688–699. [Google Scholar] [CrossRef]
- Wester, H.J.; Schoultz, B.W.; Hultsch, C.; Henriksen, G. Fast and repetitive in-capillary production of [18F]FDG. Eur. J. Nucl. Med. Mol. Imaging 2009, 36, 653–658. [Google Scholar] [CrossRef]
- 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. 2010, 37, 547–555. [Google Scholar] [CrossRef]
- Liu, K.; Lepin, E.J.; Wang, M.W.; Guo, F.; Lin, W.Y.; Chen, Y.C.; Sirk, S.J.; Olma, S.; Phelps, M.E.; Zhao, X.Z.; et al. Microfluidic-Based 18F-Labeling of Biomolecules for Immuno-Positron Emission Tomography. Mol. Imaging 2010, 10, 168–176. [Google Scholar]
- Yokell, D.L.; Leece, A.K.; Lebedev, A.A.; Miraghaie, R.R.; Ball, C.E.; Zhang, J.J.; Kolb, H.C.; Elizarov, A.A.; Mahmood, U.U. Microfluidic single vessel production of hypoxia tracer 1H-1-(3-[(18)F]-fluoro-2-hydroxy-propyl)-2-nitro-imidazole ([(18)F]-FMISO). Appl. Radiat. Isot. 2012, 70, 2313–2316. [Google Scholar] [CrossRef]
- Rensch, C.; Waengler, B.; Yaroshenko, A.; Samper, V.; Baller, M.; Heumesser, N.; Ulin, J.; Riese, S.; Reischl, G. Microfluidic reactor geometries for radiolysis reduction in radiopharmaceuticals. Appl. Radiat. Isot. 2012, 70, 1691–1697. [Google Scholar] [CrossRef]
- Yu, S. Review of 18F-FDG Synthesis and Quality Control. Biomed. Imaging Interv. J. 2006, 2, e57. [Google Scholar]
- Zimmermann, R.G. Why are investors not interested in my radiotracer? The industrial and regulatory constraints in the development of radiopharmaceuticals. Nucl. Med. Biol. 2013, 40, 155–166. [Google Scholar] [CrossRef]
- Hamacher, K.; Coenen, H.H.; Stöcklin, G. Efficient stereospecific synthesis of no-carrier-added 2-[18F]-fluoro-2-deoxy-d-glucose using aminopolyether supported nucleophilic substitution. J. Nucl. Med. 1986, 27, 235–238. [Google Scholar]
- Machulla, H.-J.; Blocher, A.; Kuntzsch, M.; Piert, M.; Wei, R.; Grierson, J. R. Simplified Labeling Approach for Synthesizing 3'-Deoxy-3'-[18F]Fluorothymidine ([18F]FLT). J. Radioanal. Nucl. Chem. 2000, 243, 843–846. [Google Scholar] [CrossRef]
- Elizarov, A.M. Microreactors for radiopharmaceutical synthesis. Lab Chip 2009, 9, 1326–1333. [Google Scholar] [CrossRef]
- Wang, M.W.; Lin, W.Y.; Liu, K.; Masterman-Smith, M.; Shen, C.K.-F. Microfluidics for Positron Emission Tomography Probe Development. Mol. Imaging 2010, 9, 175–191. [Google Scholar]
- Keng, P.Y.; Esterby, M.; van Dam, R.M. Emerging Technologies for Decentralized Production of PET Tracers. In Positron Emission Tomography - Current Clinical and Research Aspects, 1st ed.; InTech: New York, NY, USA, 2012; pp. 153–182. [Google Scholar]
- Liow, E.; O’Brien, A.; Luthra, S.; Brady, F.; Steel, C. Preliminary studies of conducting high level production radiosyntheses using microfluidic devices. Label. Compd. Radiopharm. 2005, 48, 28. [Google Scholar]
- Steel, C.J.; O'Brien, A.T.; Luthra, S. K.; Brady, F. Automated PET radiosyntheses using microfluidic devices. J. Label. Compd. Radiopharm. 2007, 50, 308–311. [Google Scholar] [CrossRef]
- Padgett, H. C.; Buchanan, C. R.; Collier, T. L.; Matteo, J. C.; Alvord, C. W. Microfluidic apparatus and method for synthesis of molecular imaging probes. U.S. Patent 2005/0232387 A1, 20 October 2005. [Google Scholar]
- Selivanova, S.V.; Mu, L.; Ungersboeck, J.; Stellfeld, T.; Ametamey, S.M.; Schibli, R.; Wadsak, W. Single-step radiofluorination of peptides using continuous flow microreactor. Org. Biomol. Chem. 2012, 10, 3871–3874. [Google Scholar] [CrossRef]
- Lu, S.-Y.; Watts, P.; Chin, F.T.; Hong, J.; Musachio, J.L.; Briard, E.; Pike, V.W. Syntheses of 11C- and 18F-labeled carboxylic esters within a hydrodynamically-driven micro-reactor. Lab Chip 2004, 4, 523–525. [Google Scholar] [CrossRef]
- Miller, P.W.; Audrain, H.; Bender, D.; deMello, A.J.; Gee, A.D.; Long, N.J.; Vilar, R. Rapid Carbon-11 Radiolabelling for PET Using Microfluidics. Chem. Eur. J. 2011, 17, 460–463. [Google Scholar] [CrossRef]
- Gillies, J.M.; Prenant, C.; Chimon, G.N.; Smethurst, G.J.; Dekker, B.A.; Zweit, J. Microfluidic technology for PET radiochemistry. Appl. Radiat. Isot. 2006, 64, 333–336. [Google Scholar] [CrossRef]
- Wheeler, T.D.; Zeng, D.X.; Desai, A.V.; Onal, B.; Reichert, D.E.; Kenis, P.J.A. Microfluidic labeling of biomolecules with radiometals for use in nuclear medicine. Lab Chip 2010, 10, 3387–3396. [Google Scholar] [CrossRef]
- Gaja, V.; Gomez-Vallejo, V.; Cuadrado-Tejedor, M.; Borrell, JI.; Llop, J. Synthesis of 13N-labelled radiotracers by using microfluidic technology. J. Labelled Comp. Radiopharm. 2012, 55, 332–338. [Google Scholar]
- Simms, R.W.; Causey, P.W.; Weaver, D.M.; Sundararajan, C.; Stephenson, K.A.; Valliant, J.F. Preparation of technetium-99m bifunctional chelate complexes using a microfluidic reactor: A comparative study with conventional and microwave labeling methods. J. Labelled Comp. Radiopharm. 2012, 55, 18–22. [Google Scholar] [CrossRef]
- Haroun, S.; Sanei, Z.; Jivan, S.; Schaffer, P.; Ruth, T.J.; Lia, P.C.H. Continuous-flow synthesis of [11C]raclopride, a positron emission tomography radiotracer, on a microfluidic chip. Can. J. Chem. 2013, 91, 326–332. [Google Scholar] [CrossRef]
- Pascali, G.; Watts, P.; Salvadori, P.A. Microfluidics in radiopharmaceutical chemistry. Nucl. Med. Biol. 2013. [Google Scholar] [CrossRef]
- Elizarov, A.M.; van Dam, M.R.; Young, S.S.; Kolb, H.C.; Padgett, H.C.; Stout, D.; Shu, J.; Huang, J.; Daridon, A.; Heath, J.R. Design and Optimization of Coin-Shaped Microreactor Chips for PET Radiopharmaceutical Synthesis. J. Nucl. Med. 2010, 51, 282–287. [Google Scholar] [CrossRef]
- Bejot, R.; Elizarov, A.M.; Ball, E. Batchmode microfluidic radiosynthesis of N-succinimidyl-4-F-18 fluorobenzoate for protein labelling. J. Labelled Comp. Radiopharm. 2011, 54, 117–122. [Google Scholar] [CrossRef]
- Collier, T.; Akula, M.; Kabalka, G. Microfluidic synthesis of [18F]FMISO. J. Nucl. Med. 2010, 51, 1462. [Google Scholar]
- Lu, S.-Y.; 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. 2009, 2, 49–55. [Google Scholar] [CrossRef]
- Lu, S.-Y.; Pike, V.W. Synthesis of [18F]xenon difluoride as a radiolabeling reagent from [18F]fluoride ion in a micro-reactor and at production scale. J. Fluorine Chem. 2010, 131, 1032–1038. [Google Scholar] [CrossRef]
- Ungersboeck, J.; Richter, S.; Collier, L.; Mitterhauser, M.; Karanikas, G.; Lanzenberger, R.; Dudczak, R.; Wadsak, W. Radiolabeling of F-18 altanserin—A microfluidic approach. Nucl. Med. Biol. 2012, 39, 1087–1092. [Google Scholar] [CrossRef]
- Ungersboeck, J.; Philippe, C.; Mien, L.K.; Haeusler, D.; Shanab, K.; Lanzenberger, R.; Spreitzer, H.; Keppler, B.K.; Dudczak, R.; Kletter, K.; Mitterhauser, M.; Wadsak, W. Microfluidic preparation of [18F]FE@SUPPY and [18F]FE@SUPPY:2—Comparison with conventional radiosyntheses. Nucl. Med. Biol. 2011, 38, 427–434. [Google Scholar] [CrossRef]
- Ungersboeck, J.; Philippe, C.; Haeusler, D.; Mitterhauser, M.; Lanzenberger, R.; Dudczak, R.; Wadsak, W. Optimization of [11C]DASB-synthesis: vessel-based and flow-through microreactor methods. Appl. Radiat. Isot. 2012, 70, 2615–2620. [Google Scholar] [CrossRef]
- Chun, J.H.; Lu, S.; Lee, Y.S.; Pike, V.W. Fast and High-yield Micro-reactor Syntheses of Ortho-substituted [18F]Fluoroarenes from Reactions of [18F]Fluoride Ion with Diaryliodonium Salts. J. Org. Chem. 2010, 75, 3332–3338. [Google Scholar] [CrossRef]
- Chun, J.H.; Pike, V.W. Selective syntheses of no-carrier-added 2- and 3-[18F]fluorohalopyridines through the radiofluorination of halopyridinyl(4[prime or minute]-methoxyphenyl)iodonium tosylates. Chem. Commun. 2012, 48, 9921–9923. [Google Scholar] [CrossRef]
- Bouvet, V.; Wuest, M.; Tam, P.H.; Wang, M.; Wuest, F. Microfluidic technology: An economical and versatile approach for the synthesis of O-(2-F-18 fluoroethyl)-ltyrosine (F-18 FET). Bioorg. Med. Chem. Lett. 2012, 22, 2291–2295. [Google Scholar] [CrossRef]
- Bouvet, V.R.; Wuest, M.; Wiebe, L.I.; Wuest, F. Synthesis of hypoxia imaging agent 1-(5-eoxy-5-fluoro-α-d-arabinofuranosyl)-2-nitroimidazole using microfluidic technology. Nucl. Med. Biol. 2011, 38, 235–245. [Google Scholar] [CrossRef]
- Telu, S.; Chun, J.H.; Simeon, F.G.; Lu, S.; Pike, V.W. Syntheses of mGluR5 PET radioligands through the radiofluorination of diaryliodonium tosylates. Org. Biomol. Chem. 2011, 9, 6629–6638. [Google Scholar] [CrossRef]
- 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. 2011, 38, 637–644. [Google Scholar] [CrossRef]
- Anderson, H.; Pillarsetty, N.; Cantorias, M.; Lewis, J.S. Improved synthesis of 2′-deoxy-2′-[18F]-fluoro-1-β-d-arabinofuranosyl-5-iodouracil ([18F]-FIAU). Nucl. Med. Biol. 2010, 37, 439–442. [Google Scholar] [CrossRef]
- Philippe, C.; Ungersboeck, J.; Schirmer, E.; Zdravkovic, M.; Nics, L.; Zeilinger, M.; Shanab, K.; Lanzenberger, R.; Karanikas, G.; Spreitzer, H.; et al. [18F]FE@SNAP—A new PET tracer for the melanin concentrating hormone receptor 1 (MCHR1): microfluidic and vessel-based approaches. Bioorg. Med. Chem. 2012, 20, 5936–5940. [Google Scholar] [CrossRef]
- Dahl, K.; Schou, M.; Halldin, C. Radiofluorination and reductive amination using a microfluidic device. J. Labelled Compd. Radiopharm. 2012, 55, 455–459. [Google Scholar] [CrossRef]
- Kealey, S.; Plisson, C.; Collier, T.L.; Long, N.J.; Husbands, S.M.; Martarello, L.; Gee, A.D. Microfluidic reactions using [11C]carbon monoxide solutions for the synthesis of a positron emission tomography radiotracer. Org. Biomol. Chem. 2011, 9, 3313–3319. [Google Scholar] [CrossRef]
- Richter, S.; Bouvet, V.; Wuest, M.; Bergmann, R.; Steinbach, J.; Pietzsch, J.; Neundorf, I.; Wuest, F. 18F-Labeled phosphopeptide-cell-penetrating peptide dimers with enhanced cell uptake properties in human cancer cells. Nucl. Med. Biol. 2012, 39, 1202–1212. [Google Scholar] [CrossRef]
- Lebedev, A.; Miraghaie, R.; Kotta, K.; Ball, C.E.; Zhang, J.; Buchsbaum, M.S.; Kolb, H.C.; Elizarov, A. Batch-reactor microfluidic device: first human use of a microfluidically produced PET radiotracer. Lab Chip 2013, 13, 136–145. [Google Scholar] [CrossRef]
- Gillies, J.M.; Prenant, C.; Chimon, G.N.; Smethurst, G.J.; Perrie, W.; Hamblett, I.; Dekker, B.; Zweit, J. Microfluidic reactor for the radiosynthesis of PET radiotracers. Appl. Radiat. Isot. 2006, 64, 325–332. [Google Scholar] [CrossRef]
- Ball, C.E.; Diener, L.T.; Elizarov, A.M.; Ford, S.; Kolb, H.C.; Miraghaie, R.; van Dam, R.M.; Zhang, J. Microfluidic radiosynthesis system for positron emission tomography biomarkers. U.S. Patent 8071035 B2, 6 December 2011. [Google Scholar]
- Zeng, D.; Desai, A.V.; Ranganathan, D.; Wheeler, T.D.; Kenis, P.J.A.; Reichert, D.E. Microfluidic radiolabeling of biomolecules with PET radiometals. Nucl. Med. Biol. 2013, 40, 42–51. [Google Scholar] [CrossRef]
- Miller, P.W.; Long, N.J.; de Mello, A.J.; Vilar, R.; Passchier, J.; Gee, A. Rapid formation of amides via carbonylative coupling reactions using a microfluidic device. Chem. Commun. (Camb.) 2006, 5, 546–548. [Google Scholar]
- Miller, P.W.; Jennings, L.E.; deMello, A.J.; Gee, A.D.; Long, N.J.; Vilar, R. A microfluidic approach to the rapid screening of palladium-catalysed aminocarbonylation reactions. Adv. Synth. Catal. 2009, 351, 3260–3268. [Google Scholar] [CrossRef]
- Arima, V.; Pascali, G.; Lade, O.; Kretschmer, H.; Bernsdorf, I.; Hammond, V.; Watts, P.; de Leonardis, F.; Tarn, M.; Pamme, N.; et al. Radiochemistry on chip: towards dose-on-demand synthesis of PET radiopharmaceuticals. Lab Chip 2013, 13, 2328–2336. [Google Scholar] [CrossRef]
- Lee, C.; Sui, G.; Elizarov, A.M.; Shu, C.J.; Shin, Y.; Dooley, A.N.; Huang, J.; Daridon, A.; Wyatt, P.; Stout, D.; et al. Multistep Synthesis of a Radiolabeled Imaging Probe Using Integrated Microfluidics. Science 2005, 310, 1793–1796. [Google Scholar] [CrossRef]
- Keng, P.Y.; Chen, S.; Ding, H.; Sadeghi, S.; Shah, G.J.; Dooraghi, A.; Phelps, M.E.; Satyamurthy, N.; Chatziioannou, A.F.; et al. Micro-chemical synthesis of molecular probes on an electronic microfluidic device. PNAS 2012, 109, 690–695. [Google Scholar] [CrossRef]
- Kim, H.K.; Chen, S.; Javed, M.R.; Lei, J.; Kim, C.-J.; Keng, P.Y.; van Dam, R.M. Multi-step organic synthesis of four different molecular probes in digital microfluidic devices. In Proceedings of International Conference on Miniaturized Systems for Chemistry and Life Sciences (mTAS), Okinawa, Japan, 2012; pp. 617–619.
- Le, S.J.; Sundararajan, N. Microfabrication for Microfluidics, 1st ed.; Artech House: Boston, MA, USA, 2010; pp. 3–5. [Google Scholar]
- Kinzl, M.; Lade, O.; Schultz, C.P.; Steckenborn, A.; Thalmann, F. Method for producing a radiopharmaceutical. WO2010/112550A1, 7 October 2010. [Google Scholar]
- Wängler, C.; Niedermoser, S.; Chin, J.; Orchowski, K.; Schirrmacher, E.; Jurkschat, K.; Iovkova-Berends, L.; Kostikov, A.P.; Schirrmacher, R.; Wängler, B. One-step (18)F-labeling of peptides for positron emission tomography imaging using the SiFA methodology. Nat. Protoc. 2012, 7, 1946–1955. [Google Scholar] [CrossRef]
- Patt, M.; Kuntzsch, M.; Machulla, H.-J. Preparation of [18F]fluoromisonidazole by nucleophilic substitution on THP-protected precursor: Yield dependence on reaction parameters. J. Radioanal. Nucl. Chem. 1999, 240, 925–927. [Google Scholar] [CrossRef]
- Chen, S.; Javed, R.; Lei, J.; Kim, H.-K.; Flores, G.; van Dam, R. M.; Keng, P. Y.; Kim, C.-J. Synthesis of diverse tracers on EWOD microdevice for positron emission tomography (PET). In Technical Digest of the Solid-State Sensor and Actuator workshop, Hilton Head Island, SC, USA, 3–7 June 2012; pp. 189–192.
- Zacheo, A.; Arima, V.; Pascali, G.; Salvadori, P.; Zizzari, A.; Perrone, E.; de Marco, L.; Gigli, G.; Rinaldi, R. Radioactivity resistance evaluation of polymeric materials for application in radiopharmaceutical production at microscale. Microfluid. Nanofluid. 2011, 11, 35–44. [Google Scholar] [CrossRef]
- Fiorini, G.S.; Daniel, T. Disposable microfluidic devices: fabrication, function, and application. BioTechniques 2005, 38, 429–446. [Google Scholar] [CrossRef]
- Füchtner, F.; Preusche, S.; Mäding, P.; Zessin, J.; Steinbach, J. Factors affecting the specific activity of [18F]fluoride from a [18O]water target. Nuklearmedizin 2008, 47, 116–119. [Google Scholar]
- Link, J.M.; Shoner, S.C.; Krohn, K.A. Sources of carrier F-19 in F-18 fluoride. AIP Conf. Proc. 2012, 1509, 61–65. [Google Scholar] [CrossRef]
- 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. 2012, 39, 601–608. [Google Scholar] [CrossRef]
- Berridge, M. S.; Apana, S. M.; Hersh, J. M. Teflon radiolysis as the major source of carrier in fluorine-18. J. Label Compd. Radiopharm. 2009, 52, 543–548. [Google Scholar] [CrossRef]
- Unger, M.A.; Chou, H.P.; Thorsen, T.; Scherer, A.; Quake, S.R. Monolithic microfabricated valves and pumps by multilayer soft lithography. Science 2000, 288, 113–116. [Google Scholar] [CrossRef]
- Sollier, E.; Murray, C.; Maoddi, P.; Di Carlo, D. Rapid prototyping polymers for microfluidic devices and high pressure injections. Lab Chip 2011, 11, 3752–3765. [Google Scholar] [CrossRef]
- Lee, J.N.; Park, C.; Whitesides, G.M. Solvent Compatibility of Poly(dimethylsiloxane)-Based Microfluidic Devices. Anal. Chem. 2003, 75, 6544–6554. [Google Scholar] [CrossRef]
- Elizarov, A.M.; Ball, C.E.; Zhang, J.; Kolb, H.C.; Van Dam, M.R.; Diener, L.; Ford, S.; Miraghaie, R. Portable Microfluidic Radiosynthesis System for Positron Emission Tomography Biomarkers and Program Code. U.S. Patent Application 2011/0097245 A1, 2011. [Google Scholar]
- Mukhopadhyay, R. When PDMS isn’t the best. Anal. Chem. 2007, 79, 3248–3253. [Google Scholar] [CrossRef]
- Huang, Y.; Castrataro, P.; Lee, C.C.; Quake, S.R. Solvent resistant microfluidic DNA synthesizer. Lab Chip 2007, 7, 24–26. [Google Scholar] [CrossRef]
- Rolland, J.P.; van Dam, R.M.; Schorzman, D.A.; Quake, S.R.; De Simone, J.M. Solvent resistant photocurable “Liquid Teflon” for micro fluidic device fabrication. J. Am. Chem. Soc. 2004, 126, 2322–2323. [Google Scholar] [CrossRef]
- Koranda, M. Kunststoff-Know how: Basis für Lab-on-Chips zur Zielgen-Anreicherung. Laborwelt 2012, 1, 20–21. [Google Scholar]
- Sasakia, H.; Onoe, H.; Osakia, T.; Kawanoa, R.; Takeuchia, S. Parylene-coating in PDMS microfluidic channels prevents the absorption of fluorescent dyes. Sens. Act. B Chem. 2010, 150, 478–482. [Google Scholar] [CrossRef]
- Steigert, J.; Haeberle, S.; Brenner, T.; Mueller, C.; Steinert, C.P.; Koltay, P.; Gottschlich, N.; Reinecke, H.; Rühe, J.; Zengerle, R.; Ducree, J. Rapid prototyping of microfluidic chips in COC. J. Micromech. Microeng. 2007, 17, 333–341. [Google Scholar] [CrossRef]
- Attia, U. M.; Marsona, S.; Alcockb, J. R. Micro-Injection moulding of polymer microfluidic devices. Microfluid. Nanofluid. 2009, 7, 1–28. [Google Scholar] [CrossRef] [Green Version]
- Mark, D.; Haeberle, S.; Roth, G.; von Stetten, F.; Zengerle, R. Microfluidic Lab-on-a-Chip Platforms: Requirements, Characteristics and Applications. In Microfluidics based microsystems—Fundamentals and Applications; Kakaç, S., Kosoy, B., Li, D., Pramuanjaroenkij, A., Eds.; Springer: Dordrecht, The Netherlands, 2010; pp. 305–376. [Google Scholar]
- Haeberle, S.; Zengerle, R. Microfluidic platforms for lab-on-a-chip applications. Lab Chip 2007, 7, 1094–1110. [Google Scholar] [CrossRef]
- Voccia, S.; Morelle, J.; Aerts, J.; Lemaire, C.; Luxen, A.; Phillipart, G. Mini-fluidic chip for the total synthesis of PET tracers. J. Labelled Comp. Radiopharm. 2009, 52, i–xliii. [Google Scholar] [CrossRef]
- Fair, R.B. Digital microfluidics: is a true lab-on-a-chip possible? Microfluid. Nanofluid. 2007, 3, 245–281. [Google Scholar] [CrossRef]
- Rensch, C.; Wängler, B.; Boeld, C.; Baller, M.; Samper, V.; Heumesser, N.; Ehrlichmann, W.; Riese, S.; Reischl, G. [18F]FMISO Synthesis on a chip-based microfluidic research platform. J. Nucl. Med. 2011, 52, 288. [Google Scholar]
- Gorkin, R.; Park, J.; Siegrist, J.; Amasia, M.; Lee, B.S.; Park, J.M.; Kim, J.; Kim, H.; Madou, M.; Cho, Y.K. Centrifugal microfluidics for biomedical applications. Lab Chip 2010, 10, 1758–1773. [Google Scholar] [CrossRef]
- Ding, H.; Sadeghi, S.; Shah, G.J.; Chen, S.; Keng, P.Y.; Kim, C.J.; van Dam, R.M. Accurate dispensing of volatile reagents on demand for chemical reactions in EWOD chips. Lab Chip 2012, 12, 3331–3340. [Google Scholar] [CrossRef]
- Hoffmann, J.; Mark, D.; Lutz, S.; Zengerle, R.; von Stetten, F. Pre-storage of liquid reagents in glass ampoules for DNA extraction on a fully integrated lab-on-a-chip cartridge. Lab Chip 2010, 10, 1480–1484. [Google Scholar] [CrossRef]
- Disch, A.; Mueller, C.; Reinecke, H. Low Cost Production of Disposable Microfluidics by Blister Packaging Technology. Conf. Proc. IEEE Eng. Med. Biol. Soc. 2007, 6322–6325. [Google Scholar]
- Fredrickson, C.K.; Fan, Z.H. Macro-to-micro interfaces for microfluidic devices. Lab Chip 2004, 4, 526–533. [Google Scholar] [CrossRef]
- Lee, C.Y.; Chang, C.L.; Wang, Y.N.; Fu, L.M. Microfluidic Mixing: A Review. Int. J. Mol. Sci. 2011, 12, 3263–3287. [Google Scholar] [CrossRef]
- Brady, F.; Luthra, S.K.; Gillies, J.M.; Geffery, N.T. Use of microfabricated devices. U.S. Patent 2005/0226776 A1, 14 March 2003. [Google Scholar]
- Samper, V.; Riese, S.; Rensch, C.; Boeld, C.; Reischl, G.; Heumesser, N.; Baller, M. Numerical simulation of heat transfer in conventional vs. microfluidic reactors and experimental benefits for [18F]PET tracer synthesis. In 9th World Molecular Imaging Congress (WMIC); 2009. P 0848. [Google Scholar]
- Stone-Elander, S.; Elander, N. Microwave application in radiolabeling with short-lived positron-emitting radionuclides. J. Label. Compd. Radiopharm. 2002, 45, 715–746. [Google Scholar] [CrossRef]
- Guo, N.; Alagille, D.; Tamagnan, G.; Price, R.R.; Baldwin, R.M. Microwave-induced nucleophilic [18F]fluorination on aromatic rings: Synthesis and effect of halogen on [18F]fluoride substitution of meta-halo (F, Cl, Br, I)-benzonitrile derivatives. Appl. Rad. Isot. 2008, 66, 1396–1402. [Google Scholar] [CrossRef]
- Mandap, K. S.; Ido, T.; Kiyono, Y.; Kobayashi, M.; Lohith, T. G.; Mori, T.; Kasamatsu, S.; Kudo, T.; Okazawa, H.; Fujibayashi, Y. Development of microwave-based automated nucleophilic [18F]fluorination system and its application to the production of [18F]flumazenil. Nucl. Med. Biol. 2009, 36, 403–409. [Google Scholar] [CrossRef]
- Scott, P.J.H.; Shao, X. Fully automated, high yielding production of N-succinimidyl 4-[18F]fluorobenzoate ([18F]SFB), and its use in microwave-enhanced radiochemical coupling reactions. J. Label. Compd. Radiopharm. 2010, 53, 586–591. [Google Scholar] [CrossRef]
- Hou, S.; Phung, D.L.; Lin, W.Y.; Wang, M.W.; Liu, K.; Shen, C.K. Microwave-assisted one-pot synthesis of N-succinimidyl-4[18F]fluorobenzoate ([18F]SFB). J. Vis. Exp. 2011, 52, 2755. [Google Scholar]
- Kumar, P.; Wiebe, L.I.; Asikoglu, M.; Tandon, M.; McEwan, A.J. Microwave-assisted (radio)halogenation of nitroimidazole-based hypoxia markers. Appl. Radiat. Isot. 2002, 57, 697–703. [Google Scholar] [CrossRef]
- Hwang, D.R.; Moerlein, S.M.; Welch, M.J. Microwave-facilitated synthesis of [18F]-Spiperone. J. Lab. Compd. Radiopharm. 1989, 26, 391. [Google Scholar] [CrossRef]
- Oh, K.; Sklavounos, A.H.; Marchiarullo, D.J.; Barker, N.S.; Landers, J.P. Microwave-assisted polymerade chain reaction (PCR) in disposable microdevices. In 15th International Conference on Miniaturized Systems for Chemistry and Life Sciences, Seattle, WA, USA, 2011; pp. 305–307.
- Seo, J.W.; Lee, B.S.; Lee, S.J.; Oh, S.J.; Chi, D.Y. Fast and Easy Drying Method for the Preparation of Activated [18F]Fluoride Using Polymer Cartridge. Bull. Korean Chem. Soc. 2011, 32, 71–76. [Google Scholar] [CrossRef]
- Lee, S.J.; Oh, S.J.; Chi, D.Y.; Kang, S.H.; Kil, H.S.; Kim, J.S.; Moon, D.H. One-step high-radiochemical-yield synthesis of [18F]FP-CIT using a protic solvent system. Nucl. Med. Biol. 2007, 34, 345–351. [Google Scholar] [CrossRef]
- Kim, D.W.; Ahn, D.S.; Oh, Y.H.; Lee, S.; Kil, H.S.; Oh, S.J.; Lee, S.J.; Kim, J.S.; Ryu, J.S.; Moon, D.H.; et al. A New Class of SN2 Reactions Catalyzed by Protic Solvents: Facile Fluorination for Isotopic Labeling of Diagnostic Molecules. Am. Chem. Soc. 2006, 128, 16394–16397. [Google Scholar] [CrossRef]
- Wester, H.J.; Henriksen, G.; Wessmann, S. Method for the direct elution of reactive [18F]fluoride from an anion exchange resin in an organic medium suitable for radiolabelling without any evaporation step by the use of alkalimetal and alkaline earth metal cryptates. WO2011141410A1, 9 May 2011. [Google Scholar]
- Wessmann, S.H.; Henriksen, G.; Wester, H.J. Cryptate mediated nucleophilic 18F-fluorination without azeotropic drying. Nuklearmedizin 2012, 51, 1–8. [Google Scholar]
- Eshima, D.B.; Husnu, M.; Padgett, H.; Klausing, T.A.; Bouton, C.E.; Benecke, H.; Garbark, D.B. Methods and compositions for drying in the preparation of radiopharmaceuticals. WO2013012817A1, 16 July 2012. [Google Scholar]
- Lemaire, C.; Voccia, S.; Aerts, J.; Luxen, A.; Morelle, J.L.; Philipart, G. Method for the direct elution of reactive 18f fluoride from an anion exchange resin in an organic medium suitable for radiolabelling without any evaporation step by the use of strong organic bases. WO2009003251A1, 1 July 2008. [Google Scholar]
- Toorongian, S.A.; Mulholland, G.K; Jewett, D.M.; Bachelor, M.A.; Kilbourn, M.R. Routine production of 2-deoxy-2-18F fluoro-dglucose by direct nucleophilic exchange on a quaternary 4-aminopyridinium resin. Int. J. Rad. Appl. Instrum. B 1990, 17, 273–279. [Google Scholar]
- Aerts, J.; Voccia, S.; Lemaire, C.; Giacomelli, F.; Goblet, D.; Thonon, D.; Plenevaux, A.; Warnock, G.; Luxen, A. Fast production of highly concentrated reactive [18F] fluoride for aliphatic and aromatic nucleophilic radiolabelling. Tetrahedron. Lett. 2010, 51, 64–66. [Google Scholar] [CrossRef]
- Voccia, S.; Aerts, J.; Lemaire, C.; Luxen, A.; Morelle, J. L.; Philippart, G. Method for the preparation of reactive [18F]fluoride. EP1990310A1, 23 April 2007. [Google Scholar]
- Fortt, R.; Liow, E.; Riese, S.; Steel, C. Nucleophilic radiofluorination using microfabricated devices. WO 2008/140616A3, 20 December 2007. [Google Scholar]
- De Leonardis, F.; Pascali, G.; Salvadori, P.A.; Watts, P.; Pamme, N. On-chip pre-concentration and complexation of [18F]fluoride ions via regenerable anion exchange particles for radiochemical synthesis of Positron Emission Tomography tracers. J. Chromatogr. A 2011, 1218, 4714–4719. [Google Scholar]
- De Leonardis, F.; Pascali, G.; Salvadori, P.A.; Watts, P.; Pamme, N. Microfluidic modules for [18F-] activation - Towards an integrated modular lab on a chip for PET radiotracer synthesis. Proc. MicroTAS 2010, 1604–1606. [Google Scholar]
- Ismail, R.; Park, K.-J.; van Dam, M.R.; Keng, P. Functional polymer monoliths towards solid phase radiosynthesis on microfluidic chip. J. Nucl. Med. 2012, 53, 572. [Google Scholar]
- Cvetkovic, B.; Lade, O.; Marra, L.; Arima, V.; Rinaldi, R.; Dittrich, P.S. Nitrogen supported solvent evaporation using continuous flow microfluidics. RSC Adv. 2012, 29, 11117–11122. [Google Scholar]
- Hamacher, K.; Hirschfelder, T.; Coenen, H.H. Electrochemical cell for separation of [18F]fluoride from irradiated 18O-water and subsequent no carrier added nucleophilic fluorination. Appl. Radiat. Isot. 2002, 56, 519–523. [Google Scholar] [CrossRef]
- Hamacher, K.; Coenen, H.H. No-carrier-added nucleophilic 18F-labelling in an electrochemical cell exemplified by the routine production of [18F]altanserin. Appl. Radiat. Isot. 2006, 64, 989–994. [Google Scholar] [CrossRef]
- Alexoff, D.; Schlyer, D.J.; Wolf, A.P. Recovery of [18F]fluoride from [18O]water in an electrochemical cell. Int. J. Rad. Appl. Instrum. A 1989, 40, 1–6. [Google Scholar] [CrossRef]
- Baller, M.; Samper, V.; Rensch, C.; Boeld, C. Elechtrochemical Phase Transfer Devices and Methods. WO 2011/006166A1, 12 July 2010. [Google Scholar]
- Wong, R.; Iwata, R.; Saiki, H.; Furumoto, S.; Ishikawa, Y.; Ozeki, E. Reactivity of electrochemically concentrated anhydrous F-18 fluoride for microfluidic radiosynthesis of F-18-labeled compounds. Appl. Radiat. Isot. 2012, 70, 193–199. [Google Scholar] [CrossRef]
- Saiki, H.; Iwata, R.; Nakanishi, H.; Wong, R.; Ishikawa, Y.; Furumoto, S.; Yamahara, R.; Sakamoto, K.; Ozeki, E. Electrochemical concentration of no-carrier-added [(18)F]fluoride from [(18)O]water in a disposable microfluidic cell for radiosynthesis of (18)F-labeled radiopharmaceuticals. Appl. Radiat. Isot. 2010, 68, 1703–1708. [Google Scholar] [CrossRef]
- Saito, F.; Nagashima, Y.; Goto, A.; Iwaki, M.; Takahashi, N.; Oka, T.; Inoue, T.; Hyodo, T. Electrochemical transfer of 18F from 18O water to aprotic polar solvent. Appl. Radiat. Isot. 2007, 65, 524–527. [Google Scholar] [CrossRef]
- Sadeghi, S.; Liang, V.; Cheung, S.; Woo, S.; Wu, C.; Ly, J.; Deng, Y.; Eddings, M.; van Dam, R.M. Reusable electrochemical cell for rapid separation of [18F]fluoride from [18O]water for flow-through synthesis of 18F-labeled tracers. Appl. Radiat. Isot. 2013, 75C, 85–94. [Google Scholar]
- Chun, J.H.; Pike, V.W. Single-step radiosynthesis of “18F-labeled click synthons” from azide-functionalized diaryliodonium salts. Eur. J. Org. Chem. 2012, 2012, 4541–4547. [Google Scholar] [CrossRef]
- Pascali, G.; Pitzianti, S.; Del Carlo, S.; Saccomanni, G.; Manera, M.; Macchia, M. Initial studies on the effect of water in microfluidic radiofluorinations. J. Labelled Compnd. Radiopharm. 2011, 54, S502. [Google Scholar]
- Shah, G.J.; Lei, J.; Chen, S.; Kim, C.-J.; Keng, P.Y.; van Dam, R.M. Automated injection from EWOD digital microfluidic chip into HPLC purification system. In Proceedings of International Conference on Miniaturized Systems for Chemistry and Life Sciences (mTAS), Okinawa, Japan, 2012; pp. 356–358.
- Nandy, S.K.; Rajan, M.G.R. Fully automated and simplified radiosynthesis of [18F]-3′-deoxy-3′-fluorothymidine using anhydro precursor and single neutral alumina column purification. J. Radioanal. Nucl. Chem. 2010, 283, 741–748. [Google Scholar] [CrossRef]
- Nandy, S.K.; Rajan, M.G.R. Simple, column purification technique for the fully automated radiosynthesis of [18F]fluoroazomycinarabinoside ([18F]FAZA). Appl. Radiat. Isot. 2010, 68, 1944–1949. [Google Scholar] [CrossRef]
- Zuhayra, M.; Alfteimi, A.; Forstner, C.V.; Lützen, U.; Meller, B.; Henze, E. New approach for the synthesis of [18F]fluoroethyltyrosine for cancer imaging: simple, fast, and high yielding automated synthesis. Bioorg. Med. Chem. 2009, 17, 7441–7448. [Google Scholar] [CrossRef]
- Wang, M.; Zhang, Y.; Zhang, Y.; Yuan, H. Automated synthesis of hypoxia imaging agent [18F]FMISO based upon a modified Explora FDG4 module. J. Radioanal. Nucl. Chem. 2009, 280, 149–155. [Google Scholar] [CrossRef]
- Baller, M.; De Marco, E.; Dumont, P.; Fortt, R.; Franci, X.; Kuci, S.; Samper, V.; Steel, C. Chromatography components. WO 2011/044474A1, 8 October 2010. [Google Scholar]
- Tarn, M.D.; Pascali, G.; De Leonardis, F.; Watts, P.; Salvadori, P.A.; Pamme, N. Purification of 2-[18F]fluoro-2-deoxy-d-glucose by on-chip solid-phase extraction. J. Chromatogr. A. 2013, 1280, 117–121. [Google Scholar] [CrossRef]
- Chen, S.; Lei, J.; van Dam, R.M.; Keng, P.Y.; Kim, C.-J. Planar alumina purification of 18F-labeled radiotracer synthesis on EWOD chip for positron emission tomography (PET). In 16th International Conference on Miniaturized Systems for Chemistry and Life Sciences (mTAS), Okinawa, Japan, 28 October–1 November 2012; pp. 1771–1773.
- Billen, J.; Desmet, G. Understanding and design of existing and future chromatographic support formats. J. Chromatogr. A. 2007, 1168, 73–99. [Google Scholar] [CrossRef]
- Eshima, D.; Husnu, M.; Stone, J. Method and system for automated quality control platform. WO 2013/012798 A1, 16 July 2012. [Google Scholar]
- Janus, A.; Ketzscher, U. Automatic quality control for PET and MI tracers. Available online: http://www.qc1.com/ (accessed on 21 June 2013).
- Chen, S.; Ly, J.; van Dam, R.M. Towards miniaturized quality control for 18F-labeled PET tracers: Separation of D-FAC alpha and beta anomers via capillary electrophoresis. J. Nucl. Med. 2013, 54, 1007. [Google Scholar] [CrossRef]
© 2013 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
Share and Cite
Rensch, C.; Jackson, A.; Lindner, S.; Salvamoser, R.; Samper, V.; Riese, S.; Bartenstein, P.; Wängler, C.; Wängler, B. Microfluidics: A Groundbreaking Technology for PET Tracer Production? Molecules 2013, 18, 7930-7956. https://doi.org/10.3390/molecules18077930
Rensch C, Jackson A, Lindner S, Salvamoser R, Samper V, Riese S, Bartenstein P, Wängler C, Wängler B. Microfluidics: A Groundbreaking Technology for PET Tracer Production? Molecules. 2013; 18(7):7930-7956. https://doi.org/10.3390/molecules18077930
Chicago/Turabian StyleRensch, Christian, Alexander Jackson, Simon Lindner, Ruben Salvamoser, Victor Samper, Stefan Riese, Peter Bartenstein, Carmen Wängler, and Björn Wängler. 2013. "Microfluidics: A Groundbreaking Technology for PET Tracer Production?" Molecules 18, no. 7: 7930-7956. https://doi.org/10.3390/molecules18077930