Enabling efficient PET imaging of Synaptic Vesicle glycoprotein 2A (SV2A) with a robust and one-step radiosynthesis of a highly potent 18F-labelled ligand ([18F]UCB-H)
[en] We herein describe the straightforward synthesis of a stable pyridyl(4- methoxyphenyl)iodonium salt and its [18F]radiolabelling within a one-step, fully automated and cGMP compliant radiosynthesis of [18F]UCB-H ([18F]7), a PET tracer for the imaging of Synaptic Vesicle glycoprotein 2A (SV2A). Over the course of one year, 50 automated productions provided 34±2% of injectable [18F]7 from up to 285 GBq (7.7 Ci) of [18F]fluoride in 50 minutes (uncorrected radiochemical yield. Specific Activity = 815±185 GBq/μmol). The successful implementation of our synthetic strategy within routine, high-activity and cGMP productions attests to its practicality and reliability for the production of large doses of [18F]7. In addition to enabling efficient and cost-effective clinical research on a range of neurological pathologies through the imaging of SV2A, this work further demonstrates the real value of iodonium salts for the cGMP 18F-PET tracer manufacturing industry, and their ability to fulfill practical and regulatory requirements in that field.
Research center :
Giga-CRC In vivo Imaging
Disciplines :
Life sciences: Multidisciplinary, general & others
Author, co-author :
Warnier, Corentin ; Université de Liège > Centre de recherches du cyclotron
Lemaire, Christian ; Université de Liège > Centre de recherches du cyclotron
Becker, Guillaume ; Université de Liège > Centre de recherches du cyclotron
Aerts, Joël ; Université de Liège > Centre de recherches du cyclotron
Otabashi, Muhammad
Bahri, Mohamed Ali ; Université de Liège > Département de physique > Département de physique
Mercier, Joël
Plenevaux, Alain ; Université de Liège > Département de chimie (sciences) > Département de chimie (sciences)
Luxen, André ; Université de Liège > Département de chimie (sciences) > Laboratoire de chimie organique de synthèse
Language :
English
Title :
Enabling efficient PET imaging of Synaptic Vesicle glycoprotein 2A (SV2A) with a robust and one-step radiosynthesis of a highly potent 18F-labelled ligand ([18F]UCB-H)
Publication date :
06 September 2016
Journal title :
Journal of Medicinal Chemistry
ISSN :
0022-2623
eISSN :
1520-4804
Publisher :
American Chemical Society, Washington, United States - District of Columbia
Mercier, J.; Archen, L.; Bollu, V.; Carré, S.; Evrard, Y.; Jnoff, E.; Kenda, B.; Lallemand, B.; Michel, P.; Montel, F.; Moureau, F.; Price, N.; Quesnel, Y.; Sauvage, X.; Valade, A.; Provins, L. Discovery of Heterocyclic Nonacetamide Synaptic Vesicle Protein 2A (SV2A) Ligands with Single-Digit Nanomolar Potency: Opening Avenues towards the First SV2A Positron Emission Tomography (PET) Ligands ChemMedChem 2014, 9, 693-698 10.1002/cmdc.201300482
Lynch, B. A.; Lambeng, N.; Nocka, K.; Kensel-Hammes, P.; Bajjalieh, S. M.; Matagne, A.; Fuks, B. The Synaptic Vesicle Protein SV2A Is the Binding Site for the Antiepileptic Drug Levetiracetam Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 9861-9866 10.1073/pnas.0308208101
Warnock, G. I.; Aerts, J.; Bahri, M. A.; Bretin, F.; Lemaire, C.; Giacomelli, F.; Mievis, F.; Mestdagh, N.; Buchanan, T.; Valade, A.; Mercier, J.; Wood, M.; Gillard, M.; Seret, A.; Luxen, A.; Salmon, E.; Plenevaux, A. Evaluation of 18F-UCB-H as a Novel PET Tracer for Synaptic Vesicle Protein 2A in the Brain J. Nucl. Med. 2014, 55, 1336-1341 10.2967/jnumed.113.136143
Stockburger, C.; Miano, D.; Baeumlisberger, M.; Pallas, T.; Arrey, T. N.; Karas, M.; Friedland, K.; Müller, W. E. A Mitochondrial Role of SV2a Protein in Aging and Alzheimer's Disease: Studies with Levetiracetam J. Alzheimer's Dis. 2015, 50, 201-215 10.3233/JAD-150687
WHO. Epilepsy. http://www.who.int/mediacentre/factsheets/fs999/en/ (accessed May 9, 2016).
Ametamey, S. M.; Honer, M.; Schubiger, P. A. Molecular Imaging with PET Chem. Rev. 2008, 108, 1501-1516 10.1021/cr0782426
Maisey, M. N. Positron Emission Tomography in Clinical Medicine. In Positron Emission Tomography; Bailey, D. L.; Towsend, D. W.; Valk, P. E.; Maisey, M. N., Eds.; Springer Verlag: London, 2003; pp 1-12, DOI: 10.1007/1-84628-007-9-1.
Mason, N. S.; Mathis, C. A. Radiohalogens for PET Imaging. In Positron Emission Tomography; Bailey, D. L.; Towsend, D. W.; Valk, P. E.; Maisey, M. N., Eds.; Springer Verlag: London, 2003; pp 203-222, DOI: 10.1007/1-84628-007-9-9.
Weber, W. A. Positron Emission Tomography as an Imaging Biomarker J. Clin. Oncol. 2006, 24, 3282-3292 10.1200/JCO.2006.06.6068
O'Hagan, D. Fluorine in Health Care: Organofluorine Containing Blockbuster Drugs J. Fluorine Chem. 2010, 131, 1071-1081 10.1016/j.jfluchem.2010.03.003
Adam, M. J.; Wilbur, D. S. Radiohalogens for Imaging and Therapy Chem. Soc. Rev. 2005, 34, 153-163 10.1039/b313872k
Estrada, S.; Lubberink, M.; Thibblin, A.; Sprycha, M.; Buchanan, T.; Mestdagh, N.; Kenda, B.; Mercier, J.; Provins, L.; Gillard, M.; Tytgat, D.; Antoni, G. [11C]UCB-A, a Novel PET Tracer for Synaptic Vesicle Protein 2 A Nucl. Med. Biol. 2016, 43, 325-332 10.1016/j.nucmedbio.2016.03.004
Nabulsi, N.; Mercier, J.; Holden, D.; Carre, S.; Najafzadeh, S.; Vandergeten, M.-C.; Lin, S.-F.; Deo, A. K.; Price, N.; Wood, M.; Lara-Jaime, T.; Montel, F.; Laruelle, M.; Carson, R. E.; Hannestad, J.; Huang, Y. Synthesis and Preclinical Evaluation of 11C-UCB-J as a PET Tracer for Imaging the Synaptic Vesicle Glycoprotein 2A in the Brain J. Nucl. Med. 2016, 57, 777-785 10.2967/jnumed.115.168179
Pike, V. W.; Aigbirhio, F. I. Reactions of Cyclotron-Produced [18F]fluoride with Diaryliodonium Salts-a Novel Single-Step Route to No-Carrier-Added [18F]fluoroarenes J. Chem. Soc., Chem. Commun. 1995, 21, 2215-2216 10.1039/C39950002215
Satiamurthy, N.; Barrio, J. R. No-Carrier-Added Nucleophilic [F-18] Fluorination of Aromatic Compounds. WO2010117435 A2, 2010.
Cardinale, J.; Ermert, J.; Humpert, S.; Coenen, H. H. Iodonium Ylides for One-Step, No-Carrier-Added Radiofluorination of Electron Rich Arenes, Exemplified with 4-(([18F]fluorophenoxy)-Phenylmethyl)piperidine NET and SERT Ligands RSC Adv. 2014, 4, 17293 10.1039/c4ra00674g
Rotstein, B. H.; Stephenson, N.; Vasdev, N.; Liang, S. H. Spirocyclic Hypervalent Iodine(III)-Mediated Radiofluorination of Non-Activated and Hindered Aromatics Nat. Commun. 2014, 5, 4365 10.1038/ncomms5365
Tredwell, M.; Preshlock, S. M.; Taylor, N. J.; Gruber, S.; Huiban, M.; Passchier, J.; Mercier, J.; Génicot, C.; Gouverneur, V. A General Copper-Mediated Nucleophilic 18 F Fluorination of Arenes Angew. Chem., Int. Ed. 2014, 53, 7751-7755 10.1002/anie.201404436
Lee, E.; Kamlet, A. S.; Powers, D. C.; Neumann, C. N.; Boursalian, G. B.; Furuya, T.; Choi, D. C.; Hooker, J. M.; Ritter, T. A Fluoride-Derived Electrophilic Late-Stage Fluorination Reagent for PET Imaging Science 2011, 334, 639-642 10.1126/science.1212625
Lee, E.; Hooker, J. M.; Ritter, T. Nickel-Mediated Oxidative Fluorination for PET with Aqueous [18F] Fluoride J. Am. Chem. Soc. 2012, 134, 17456-17458 10.1021/ja3084797
Carroll, M. A.; Nairne, J.; Woodcraft, J. L. Diaryliodonium Salts: A Solution to 3-[18F]fluoropyridine J. Labelled Compd. Radiopharm. 2007, 50, 452-454 10.1002/jlcr.1190
Chun, J. H.; Lu, S.; Lee, Y. S.; Pike, V. W. Fast and High-Yield Microreactor Syntheses of Ortho-Substituted [18F]fluoroarenes from Reactions of [(18)F]fluoride Ion with Diaryliodonium Salts J. Org. Chem. 2010, 75, 3332-3338 10.1021/jo100361d
Chun, J. H.; Telu, S.; Lu, S.; Pike, V. W. Radiofluorination of Diaryliodonium Tosylates under Aqueous-Organic and Cryptand-Free Conditions Org. Biomol. Chem. 2013, 11, 5094-5099 10.1039/c3ob40742j
Chun, J.-H.; Pike, V. W. Selective Syntheses of No-Carrier-Added 2- and 3-[18F]fluorohalopyridines through the Radiofluorination of halopyridinyl(4′-Methoxyphenyl)iodonium Tosylates Chem. Commun. 2012, 48, 9921 10.1039/c2cc35005j
Chun, J.-H.; Pike, V. W. Single-Step Radiosynthesis of " 18 F-Labeled Click Synthons" from Azide-Functionalized Diaryliodonium Salts Eur. J. Org. Chem. 2012, 2012, 4541-4547 10.1002/ejoc.201200695
Edwards, R.; Westwell, A. D.; Daniels, S.; Wirth, T. Convenient Synthesis of Diaryliodonium Salts for the Production of [18F]F-DOPA Eur. J. Org. Chem. 2015, 2015, 625-630 10.1002/ejoc.201403378
Edwards, R.; de Vries, W.; Westwell, A. D.; Daniels, S.; Wirth, T. Solid-Supported Iodonium Salts for Fluorinations Eur. J. Org. Chem. 2015, 2015, 6909-6916 10.1002/ejoc.201500992
Ichiishi, N.; Brooks, A. F.; Topczewski, J. J.; Rodnick, M. E.; Sanford, M. S.; Scott, P. J. H. Copper-Catalyzed [18F]Fluorination of (Mesityl)(aryl)iodonium Salts Org. Lett. 2014, 16, 3224-3227 10.1021/ol501243g
Merritt, E. A.; Olofsson, B. Diaryliodonium Salts: A Journey from Obscurity to Fame Angew. Chem., Int. Ed. 2009, 48, 9052-9070 10.1002/anie.200904689
Moon, B. S.; Kil, H. S.; Park, J. H.; Kim, J. S.; Park, J.; Chi, D. Y.; Lee, B. C.; Kim, S. E. Facile Aromatic Radiofluorination of [18F]flumazenil from Diaryliodonium Salts with Evaluation of Their Stability and Selectivity Org. Biomol. Chem. 2011, 9, 8346 10.1039/c1ob06277h
Moon, B. S.; Park, J. H.; Lee, H. J.; Lee, B. C.; Kim, S. E. Routine Production of [ 18 F]Flumazenil from Iodonium Tosylate Using a Sample Pretreatment Method: A 2.5-Year Production Report Mol. Imaging Biol. 2014, 16, 619-625 10.1007/s11307-014-0738-z
Neumann, K. D.; Qin, L.; Vāvere, A. L.; Shen, B.; Miao, Z.; Chin, F. T.; Shulkin, B. L.; Snyder, S. E.; DiMagno, S. G. Efficient Automated Syntheses of High Specific Activity 6-[18F]fluorodopamine Using a Diaryliodonium Salt Precursor J. Labelled Compd. Radiopharm. 2016, 59, 30-34 10.1002/jlcr.3367
Ross, T. L.; Ermert, J.; Hocke, C.; Coenen, H. H. Nucleophilic 18F-Fluorination of Heteroaromatic Iodonium Salts with No-Carrier-Added [18F]fluoride J. Am. Chem. Soc. 2007, 129, 8018-8025 10.1021/ja066850h
Richarz, R.; Krapf, P.; Zarrad, F.; Urusova, E. a; Neumaier, B.; Zlatopolskiy, B. D. Neither Azeotropic Drying, nor Base nor Other Additives: A Minimalist Approach to 18 F-Labeling Org. Biomol. Chem. 2014, 12, 8094-8099 10.1039/C4OB01336K
Selivanova, S. V.; Stellfeld, T.; Heinrich, T. K.; Muller, A.; Kramer, S. D.; Schubiger, P. A.; Schibli, R.; Ametamey, S. M.; Vos, B.; Meding, J.; Bauser, M.; Hutter, J.; Dinkelborg, L. M. Design, Synthesis, and Initial Evaluation of a High Affinity Positron Emission Tomography Probe for Imaging Matrix Metalloproteinases 2 and 9 J. Med. Chem. 2013, 56, 4912-4920 10.1021/jm400156p
Zlatopolskiy, B. D.; Zischler, J.; Krapf, P.; Zarrad, F.; Urusova, E. A.; Kordys, E.; Endepols, H.; Neumaier, B. Copper-Mediated Aromatic Radiofluorination Revisited: Efficient Production of PET Tracers on a Preparative Scale Chem.-Eur. J. 2015, 21, 5972-5979 10.1002/chem.201405586
Shah, A.; Pike, V. W.; Widdowson, D. A. The Synthesis of [18F]fluoroarenes from the Reaction of Cyclotron-Produced [18F]fluoride Ion with Diaryliodonium Salts J. Chem. Soc., Perkin Trans. 1 1998, 13, 2043-2046 10.1039/a802349b
Carroll, M. A.; Nairne, J.; Smith, G.; Widdowson, D. A. Radical Scavengers: A Practical Solution to the Reproducibility Issue in the Fluoridation of Diaryliodonium Salts J. Fluorine Chem. 2007, 128, 127-132 10.1016/j.jfluchem.2006.10.018
Lubinkowski, J. J.; Knapczyk, J. W.; Calderon, J. L.; Petit, L. R.; McEwen, W. E. Reactions of Diaryliodonium Salts with Sodium Alkoxides J. Org. Chem. 1975, 40, 3010-3015 10.1021/jo00909a002
Bielawski, M.; Olofsson, B. High-Yielding One-Pot Synthesis of Diaryliodonium Triflates from Arenes and Iodine or Aryl Iodides Chem. Commun. (Cambridge, U. K.) 2007, 24, 2521-2523 10.1039/b701864a
Bielawski, M.; Malmgren, J.; Pardo, L. M.; Wikmark, Y.; Olofsson, B. One-Pot Synthesis and Applications of N-Heteroaryl Iodonium Salts ChemistryOpen 2014, 3, 19-22 10.1002/open.201300042
Carroll, M. A.; Pike, V. W.; Widdowson, D. A. New Synthesis of Diaryliodonium Sulfonates from Arylboronic Acids Tetrahedron Lett. 2000, 41, 5393-5396 10.1016/S0040-4039(00)00861-3
Chun, J. H.; Pike, V. W. Regiospecific Syntheses of Functionalized Diaryliodonium Tosylates via [Hydroxy(tosyloxy)iodo]arenes Generated in Situ from (Diacetoxyiodo)arenes J. Org. Chem. 2012, 77, 1931-1938 10.1021/jo202517v
Jalalian, N.; Olofsson, B. Synthesis of Koser's Reagent and Derivatives Org. Synth. 2013, 90, 1-9 10.15227/orgsyn.090.0001
Stang, P. J.; Tykwinski, R.; Zhdankin, V. V. Preparation of Bis(heteroaryl)iodonium Salts via an Iodonium Transfer Reaction between Di(cyano)iodonium Triflate and Organostannes J. Heterocycl. Chem. 1992, 29, 815-818 10.1002/jhet.5570290424
Krasnokutskaya, E.; Semenischeva, N.; Filimonov, V.; Knochel, P. A New, One-Step, Effective Protocol for the Iodination of Aromatic and Heterocyclic Compounds via Aprotic Diazotization of Amines Synthesis 2007, 2007, 81-84 10.1055/s-2006-958936
Sunami, S.; Nishimura, T.; Nishimura, I.; Ito, S.; Arakawa, H.; Ohkubo, M. Synthesis and Biological Activities of Topoisomerase I Inhibitors, 6-Arylmethylamino Analogues of Edotecarin J. Med. Chem. 2009, 52, 3225-3237 10.1021/jm801641t
Lemaire, C.; Libert, L.; Franci, X.; Genon, J.-L.; Kuci, S.; Giacomelli, F.; Luxen, A. Automated Production at the Curie Level of No-Carrier-Added 6-[ 18 F]fluoro- L -Dopa and 2-[ 18 F]fluoro- L -Tyrosine on a FASTlab Synthesizer J. Labelled Compd. Radiopharm. 2015, 58, 281-290 10.1002/jlcr.3291
Lemaire, C.; Damhaut, P.; Lauricella, B.; Mosdzianowski, C.; Morelle, J.-L.; Monclus, M.; Van Naemen, J.; Mulleneers, E.; Aerts, J.; Plenevaux, A.; Brihaye, C.; Luxen, A. Fast [18F]FDG Synthesis by Alkaline Hydrolysis on a Low Polarity Solid Phase Support J. Labelled Compd. Radiopharm. 2002, 45, 435-447 10.1002/jlcr.572
Libert, L. C.; Franci, X.; Plenevaux, A. R.; Ooi, T.; Maruoka, K.; Luxen, A. J.; Lemaire, C. F. Production at the Curie Level of No-Carrier-Added 6-18F-Fluoro-L-Dopa J. Nucl. Med. 2013, 54, 1154-1161 10.2967/jnumed.112.112284
Guo, X.; Mittelstaedt, R. A.; Guo, L.; Shaddock, J. G.; Heflich, R. H.; Bigger, A. H.; Moore, M. M.; Mei, N. Nitroxide TEMPO: A Genotoxic and Oxidative Stress Inducer in Cultured Cells Toxicol. In Vitro 2013, 27, 1496-1502 10.1016/j.tiv.2013.02.019
European Medicines Agency. Limits of genotoxic impurities. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general-content-000738.jsp&mid=WC0b01ac0580028e8c (accessed Aug 12, 2016).
International Council for Harmonization. Impurities: Guideline for Residual Solvents (ICH Q3C (R5)). http://www.ich.org/products/guidelines (accessed Aug 12, 2016).
Amorati, R.; Pedulli, G. F.; Pratt, D. a; Valgimigli, L. TEMPO Reacts with Oxygen-Centered Radicals under Acidic Conditions Chem. Commun. (Cambridge, U. K.) 2010, 46, 5139-5141 10.1039/c0cc00547a
Pennington, J.; Cohen, R. D.; Tian, Y.; Boulineau, F. Development of an LC-MS Method for Ultra Trace-Level Determination of 2,2,6,6-Tetramethylpiperidine-1-Oxl (TEMPO), a Potential Genotoxic Impurity within Active Pharmaceutical Ingredients J. Pharm. Biomed. Anal. 2015, 114, 488-492 10.1016/j.jpba.2015.04.008
Sen, V. D.; Golubev, V. A. Kinetics and Mechanism for Acid-Catalyzed Disproportionation of 2,2,6,6-Tetramethylpiperidine-1-Oxyl J. Phys. Org. Chem. 2009, 22, 138-143 10.1002/poc.1439
Strohmeyer, H. E.; Sluggett, G. W. Determination and Control of TEMPO, a Potentially Genotoxic Free Radical Reagent Used in the Synthesis of Filibuvir J. Pharm. Biomed. Anal. 2012, 62, 216-219 10.1016/j.jpba.2011.12.036
International Council for Harmonization. Validation of Analytical Procedures: Text and Methodology (ICH Q2 (R1)). http://www.ich.org/products/guidelines/ (accessed Aug 12, 2016).
Epsztajn, J.; Plotka, M. W.; Grabowska, A. Application of Organolithium Compounds in Organic Synthesis. XIX. Synthetic Strategies Based on Aromatic Metalation. A Concise Regiospecific Synthesis of 3-Halogenated Picolinic and Isonicotinic Acids Synth. Commun. 1997, 27, 1075-1086 10.1080/00397919708003053
Armarego, W. L. F.; Chai, C. L. L. In Purification of Laboratory Chemicals; Armarego, W. L. F.; Chai, C. L. L., Eds.; Elsevier Inc.: Oxford, U.K., 2009.