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Current Radiopharmaceuticals

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ISSN (Print): 1874-4710
ISSN (Online): 1874-4729

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Research Article

Synthesis of [18F]FAZA Using Nosyl and Iodo Precursors for Nucleophilic Radiofluorination

Author(s): William Sun, Cheryl Falzon, Ebrahim Naimi, Ali Akbari, Leonard I. Wiebe*, Manju Tandon and Piyush Kumar

Volume 12, Issue 1, 2019

Page: [49 - 57] Pages: 9

DOI: 10.2174/1874471011666181019105947

Price: $65

Abstract

Background: 1-α-D-(5-Deoxy-5-[18F]fluoroarabinofuranosyl)-2-nitroimidazole ([18F]FAZA) is manufactured by nucleophilic radiofluorination of 1-α-D-(2’,3’-di-O-acetyl-5’-O-toluenesulfonylarabinofuranosyl)- 2-nitroimidazole (DiAcTosAZA) and alkaline deprotection to afford [18F]FAZA. High yields (>60%) under optimized conditions frequently revert to low yields (<20%) in large scale, automated syntheses. Competing side reactions and concomitant complex reaction mixtures contribute to substantial loss of product during HPLC clean-up.

Objective: To develop alternative precursors for facile routine clinical manufacture of [18F]FAZA that are compatible with current equipment and automated procedures.

Methods: Two new precursors, 1-α-D-(2’,3’-di-O-acetyl-5’-O-(4-nitrobenzene)sulfonyl-arabinofuranosyl)-2- nitroimidazole (DiAcNosAZA) and 1-α-D-(2’,3’-di-O-acetyl-5’-iodo-arabinofuranosyl)-2-nitroimidazole (DiAcIAZA), were synthesized from commercially-available 1-α-D-arabinofuranosyl-2-nitroimidazole (AZA). A commercial automated synthesis unit (ASU) was used to condition F-18 for anhydrous radiofluorination, and to radiofluorinate DiAcNosAZA and DiAcIAZA using the local standardized protocol to manufacture [18F]FAZA from AcTosAZA.

Results: DiAcNosAZA was synthesized via two pathways, in recovered yields of 29% and 40%, respectively. The nosylation of 1-α-D-(2’,3’-di-O-acetyl-arabinofuranosyl)-2-nitroimidazole (DiAcAZA) featured a strong competing reaction that afforded 1-α-D-(2’,3’-di-O-acetyl-5’-chloro-arabinofuranosyl)-2- nitroimidazole (DiAcClAZA) in 55% yield. Radiofluorination yields were better from DiAcNosAZA and DiAcIAZA than from DiAcTosAZA, and the presence of fewer side products afforded higher purity [18F]FAZA preparations. Several radioactive and non-radioactive by products of radiofluorination were assigned tentative chemical structures based on co-chromatography with authentic reference compounds.

Conclusion: DiAcClAZA, a major side-product in the preparation of DiAcNosAZA, and its deprotected analogue (ClAZA), are unproven hypoxic tissue radiosensitizers. DiAcNosAZA and DiAcIAZA provided good radiofluorination yields in comparison to AcTosAZA and could become preferred [18F]FAZA precursors if the cleaner reactions can be exploited to bypass HPLC purification.

Keywords: [18F]FAZA, hypoxia imaging, PET, radiofluorination, nucleophilic substitution, precursor design, azomycin nucleosides, 2-nitroimidazoles, radiosensitizers.

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[1]
Vaupel, P. Hypoxia and aggressive tumor phenotype: implications for therapy and prognosis. Oncologist, 2008, 13, 21-26.
[2]
Challapalli, A.; Carroll, L.; Aboagye, E.O. Molecular mechanisms of hypoxia in cancer. Clin. Transl. Imaging, 2017, 5, 225-253.
[3]
Hammond, E.M.; Asselin, M.C.; Forster, D.; O’Connor, J.P.B.; Senra, J.M.; Williams, K.J. The meaning, measurement and modification of hypoxia in the laboratory and the clinic. Clin. Oncol., 2014, 26, 277-288.
[4]
Krohn, K.A.; Link, J.M.; Mason, R.P. Molecular imaging of hypoxia. J. Nucl. Med., 2008, 49, 129S-148S.
[5]
Colliez, F.; Gallez, B.; Jordan, B.F. Assessing tumor oxygenation for predicting outcome in radiation oncology: A review of studies correlating tumor hypoxic status and outcome in the preclinical and clinical settings. Front. Oncol., 2017, 7, 1-16.
[6]
Adams, G.E.; Cooke, M.S. Electron-affinic Sensitization. 1. A structural basis for chemical radiosensitization in bacteria. Int. J. Radiat. Biol. Relat. Stud. Phys. Chem. Med., 1969, 15, 457-471.
[7]
Nunn, A.; Linder, K.; Strauss, W.H. Nitroimidazoles and imaging hypoxia. Europ. J. Nucl. Med., 1995, 22, 265-280.
[8]
Wiebe, L.I.; McEwan, A.J.B. Scintigraphic imaging of focal hypoxic tissue: development and clinical applications of 123I-IAZA. Brazil. Arch. Biol. Technol., 2002, 45, S89-S102.
[9]
Rajendran, J.G.; Krohn, K.A. F18 Fluoromisonidazole for imaging tumor hypoxia: imaging the microenvironment for personalized cancer therapy. Semin. Nucl. Med., 2015, 45, 151-162.
[10]
Ricardo, C.L.; Kumar, P.; Wiebe, L.I. Bifunctional metal - nitroimidazole complexes for hypoxia theranosis in cancer. J. Diag. Imag Ther., 2015, 2, 103-158.
[11]
Kumar, P.; Bacchu, V.; Wiebe, L.I. The chemistry and radiochemistry of hypoxia-specific, radiohalogenated nitroaromatic imaging probes. Sem. Nucl. Med., 2015, 45, 122-135.
[12]
Savi, A.; Incerti, E.; Fallanca, F.; Bettinardi, V.; Rossetti, F.; Monterisi, C.; Compierchio, A.; Negri, G.; Zannini, P.; Gianolli, L.; Picchio, M. First evaluation of PET-based human biodistribution and dosimetry of 18F-FAZA, a tracer for imaging tumor hypoxia. J. Nucl. Med., 2017, 58, 1224-1229.
[13]
Melsens, E.; De Vlieghere, E.; Descamps, B.; Vanhove, C.; Kersemans, K.; De Vos, F.; Goethals, I.; Brans, B.; De Wever, O.; Ceelen, W.; Pattyn, P. Hypoxia imaging with 18F-FAZA PET/CT predicts radiotherapy response in esophageal adenocarcinoma xenografts. Radiat. Oncol., 2018, 13, 39.
[14]
Servagi-Vernat, S.; Differding, S.; Hanin, F.X.; Labar, D.; Bol, A.; Lee, J.A.; Grégoire, V. A prospective clinical study of 18F-FAZA PET-CT hypoxia imaging in head and neck squamous cell carcinoma before and during radiation therapy. Eur. J. Nucl. Med. Mol. Imaging, 2014, 41, 1544-1552.
[15]
Mortensen, L.S.; Johansen, J.; Kallehauge, J.; Primdahl, H.; Busk, M.; Lassen, P.; Alsner, J.; Sørensen’, B.S.; Toustrup, K.; Jakobsen, S.; Petersen, J.; Petersen, H.; Theila, J.; Nordsmark, M.; Overgaard, J. PET imaging of hypoxia: FAZA PET/CT hypoxia imaging in patients with squamous cell carcinoma of the head and neck treated with radiotherapy: Results from the DAHANCA 24 trial. Radiother. Oncol., 2012, 105, 14-20.
[16]
Beck, R.; Röper, B.; Carlsen, J.M.; Huisman, M.C.; Lebschi, J.A.; Andratschke, N.; Picchio, M.; Souvatzoglou, M.; Machulla, H-J.; Piert, M. Pretreatment 18F-FAZA PET predicts success of hypoxia-directed radiochemotherapy using tirapazamine. J. Nucl. Med., 2007, 48, 973-980.
[17]
Grosu, A.; Souvatzoglou, M.; Röper, B.; Dobritz, M.; Wiedenmann, N.; Jacob, V.; Wester, H-J.; Reischl, G.; Machulla, H-J.; Schwaiger, M.; Molls, M.; Piert, M. Hypoxia imaging with FAZA-PET and theoretical considerations with regard to dose painting for individualization of radiotherapy in patients with head and neck cancer. Int. J. Radiat. Oncol. Biol. Phys., 2007, 69, 541-551.
[18]
Reischl, G.; Ehrlichmann, W.; Bieg, C.; Kumar, P.; Wiebe, L.I.; Machulla, H-J. Preparation of the hypoxia imaging PET tracer [18F]FAZA: reaction parameters and automation. Appl. Radiat. Isotopes., 2005, 62, 897-901.
[19]
Kumar, P.; Ortlieb, R.K.; Gupta, A.; Wiebe, L.I. Microwave-assisted radiosynthesis of the hypoxia marker 1-α-D-(5-deoxy-5-[18F]fluoroarabinofuranosyl)-2-nitroimidazole ([18F]FAZA). Curr. Radiopharm., 2014, 7, 49-56.
[20]
Bouvet, V.R.; Wuest, M.; Wiebe, L.I. Wuest, F. Synthesis of hypoxia imaging agent 1-(5-deoxy-5-fluoro-α-D-arabinofuranosyl)-2-nitroimidazole [18F]FAZA using microfluidic technology. Nucl. Med. Biol., 2011, 38, 235-245.
[21]
Hayashi, K.; Furutsuka, K.; Takei, M.; Muto, M.; Nakao, R.; Aki, H.; Suzuki, K.; Fukumura, T. High-yield automated synthesis of [18F]fluoroazomycin arabinoside ([18F]FAZA) for hypoxia-specific tumor imaging. Appl. Radiat. Isotopes., 2011, 69, 1007-1013.
[22]
Kumar, P.; Emami, S.; McEwan, A.J.B.; Wiebe, L.I. Development of an economical, single step synthesis of FAZA, a clinical hypoxia marker, and potential synthons to prepare its positional analogues. Lett. Drug Design Develop., 2009, 6, 82-85.
[23]
Jacobson, O.; Chen, X. PET designated fluoride-18 production and chemistry. Curr. Top. Med. Chem., 2010, 10, 1048-1059.
[24]
Coenen, H.H. Fluorine-18 labeling methods: features and possibilities of basic reactions. Ernst Schering Res. Found. Workshop, 2007, 15-50.
[25]
Zhang, M.R.; Suzuki, K. [18F]Fluoroalkyl agents: Synthesis, reactivity and application for development of PET ligands in molecular imaging. Curr. Top. Med. Chem., 2007, 7, 1817-1828.
[26]
Jacobson, O.; Kiesewetter, D.O.; Chen, X. Fluorine-18 radiochemistry, labeling strategies and synthetic routes. Bioconjug. Chem., 2015, 26, 1-18.
[27]
Liu, J.; Barrio, J.R.; Satyamurthy, N. Efficient synthesis of 9-(4-[18F]fluoro-3-hydroxymethyl-butyl)guanine ([18F]FHBG) and 9-[(3-[18F]fluoro-1-hydroxy-2-propoxy)methyl]guanine ([18F]FHPG). J. Fluorine . Chem., 2017, 201, 24-42.
[28]
Suehiro, M.; Vallabhajosula, S.; Goldsmith, S.J.; Ballon, D.J. Investigation of the role of the base in the synthesis of [18F]FLT. Appl. Radiat. Isotopes., 2007, 65, 1350-1358.
[29]
Mannan, R.H.; Somayaji, V.V.; Lee, J.; Mercer, J.R.; Chapman, J.D.; Wiebe, L.I. Radioiodinated 1-(5-iodo-5-deoxy-β‑D‑arabinofuranosyl)‑2‑nitroimidazole (iodoazomycin arabinoside: IAZA), a novel marker of tissue hypoxia. J. Nucl. Med., 1991, 32, 1764-1770.
[30]
Lee, H.C.; Kumar, P.; McEwan, A.J.; Wiebe, L.I.; Mercer, J.R. Synthesis, radiolabeling, and biodistribution of putative metabolites of iodoazomycin arabinoside. Nucl. Med. Biol., 2000, 27, 61-68.
[31]
Kumar, P.; Wiebe, L.I.; Atrazheva, E.; Tandon, M. An improved synthesis of alpha-AZA, alpha-AZP and alpha-AZG, the precursors to clinical markers of tissue hypoxia. Tetrahedron Lett., 2001, 42, 2077-2078.
[32]
Kumar, P.; Emami, S.; McEwan, A.J.B.; Wiebe, L.I. Development of an economical, single step synthesis of FAZA, a clinical hypoxia marker, and potential synthons to prepare its positional analogs. Lett. Drug Design . Discov., 2009, 6, 82-85.
[33]
Horwitz, J.P.; Chua, J.; Da Rooge, M.A.; Noel, M.; Klundt, I.L. Nucleosides. IX. The formation of 2′,3′-unsaturated pyrimidine nucleosides via a novel β-elimination reaction. J. Org. Chem., 1966, 31, 205-211.
[34]
Edmonton, PET Centre (EPC) data.

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