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β -[18F]Fluoro Azomycin Arabinoside (β -[18F]FAZA): Synthesis, Radiofluorination and Preliminary PET Imaging of Murine A431 Tumors

[ Vol. 10 , Issue. 2 ]

Author(s):

Piyush Kumar, Peter Roselt, Gerald Reischl, Carlene Cullinane, Davood Beiki, Walter Ehrlichmann, David Binns, Ebrahim Naimi, Jennifer Yang, Rodney Hicks, Hans-Juergen Machulla and Leonard I. Wiebe   Pages 93 - 101 ( 9 )

Abstract:


Background: 1-α-D-(5-Deoxy-5-[18F]fluoroarabinofuranosyl)-2-nitroimidazole([18F] FAZA) is a PET radiotracer that demonstrates excellent potential in imaging regional hypoxia, and is clinically used in diagnosing a wide range of solid tumors in cancer patients. [18F]FAZA, however, is radiofluorinated in only moderate recovered radiochemical yield (rRCY, ~12%). It is postulated that the relative stability of the C1’ β-anomeric bond at C5’ will make 1-β-D-(5-fluoro-5-deoxyarabinofuranosyl)-2-nitroimidazole (β-FAZA), the β-conformer of FAZA, an attractive candidate for clinical hypoxia imaging.

Objectives: The principle goals were to synthesize β-FAZA and β-Ac2TsAZA, the radiofluorination precursor, to establish the radiofluorination chemistry leading to β-[18F]FAZA, and to investigate the biodistribution of β-[18F]FAZA in an animal tumor-bearing model using PET imaging.

Methods: The appropriately-protected furanose sugar was coupled with 2-nitroimidazole to afford 1-β-D-(2,3-di-O-acetylarabinofuranosyl)-2-nitroimidazole (β-Ac2AZA). Fluorination of β-Ac2AZA with DAST, followed by alkaline hydrolysis, afforded β-FAZA (21%). The radiolabeling synthon, 1-β-D-(5-O-toluenesulfonyl-2,3-di-O-acetylarabinofuranosyl)-2-nitroimidazole (β-Ac2TsAZA), on radiofluorination using the 18F/K222 complex under various reaction conditions, followed by base-catalyzed deacetylation, afforded β-[18F]FAZA. β-[18F]FAZA was radiochemically stable for at least 8 h when stored in aqueous ethanol (8%) at 22 °C. A preliminary PET imaging-based biodistribution study of β-[18F]FAZA was performed in A431 tumor-bearing nude mice.

Results: β-FAZA and β-Ac2TsAZA were synthesized in satisfactory yield. Radiochemistry of [18F]FAZA was established. PET images showed strong uptake in hypoxic regions of the tumor.

Conclusion: The synthesis of β-FAZA and β-[18F]FAZA are reported. Radiofluorination of β-Ac2TsAZA and the deprotection of β-Ac2[18F]FAZA were facile, but led to a more complex mixture of radiofluorinated by-products than observed with the corresponding precursor of α-[18F]FAZA. PET images were indicative of hypoxia-selective accumulation of β-[18F]FAZA in tumor.

Keywords:

Hypoxia, PET imaging, β-FAZA, β-[18F]FAZA, FAZA, [18F]FAZA

Affiliation:

Department of Oncology, Cross Cancer Institute, 11560 University Avenue, Edmonton, Alberta, T6G 1Z2, Peter McCallum Cancer Institute, Melbourne, Department of Preclinical Imaging and Radiopharmacy, University of Tübingen, Tübingen, Peter McCallum Cancer Institute, Melbourne, Research Institute for Nuclear Medicine, Tehran University of Medical Sciences, Tehran 14114, Department of Preclinical Imaging and Radiopharmacy, University of Tübingen, Tübingen, Peter McCallum Cancer Institute, Melbourne, Naimi, Ebrahim Pharmacy Ltd., 9452 118 Ave NW, Edmonton, Alberta, Department of Oncology, Cross Cancer Institute, 11560 University Avenue, Edmonton, Alberta, T6G 1Z2, Peter McCallum Cancer Institute, Melbourne, Department of Preclinical Imaging and Radiopharmacy, University of Tübingen, Tübingen, Department of Oncology, Cross Cancer Institute, 11560 University Avenue, Edmonton, Alberta, T6G 1Z2

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