Synthesis and preclinical characterization of 1-(6'-deoxy-6'-[18F]fluoro-β-d-allofuranosyl)-2-nitroimidazole (β-6'-[18F]FAZAL) as a positron emission tomography radiotracer to assess tumor hypoxia.
Positron emission tomography (PET) using fluorine-18 (18F)-labeled 2-nitroimidazole radiotracers has proven useful for assessment of tumor oxygenation. However, the passive diffusion-driven cellular uptake of currently available radiotracers results in slow kinetics and low tumor-to-background ratios. With the aim to develop a compound that is actively transported into cells, 1-(6'-deoxy-6'-[18F]fluoro-β-d-allofuranosyl)-2-nitroimidazole (β-[18F]1), a putative nucleoside transporter substrate, was synthetized by nucleophilic [18F]fluoride substitution of an acetyl protected labeling precursor with a tosylate leaving group (β-6) in a final radiochemical yield of 12±8% (n=10, based on [18F]fluoride starting activity) in a total synthesis time of 60min with a specific activity at end of synthesis of 218±58GBq/μmol (n=10). Both radiolabeling precursor β-6 and unlabeled reference compound β-1 were prepared in multistep syntheses starting from 1,2:5,6-di-O-isopropylidene-α-d-allofuranose. In vitro experiments demonstrated an interaction of β-1 with SLC29A1 and SLC28A1/2/3 nucleoside transporter as well as hypoxia specific retention of β-[18F]1 in tumor cell lines. In biodistribution studies in healthy mice β-[18F]1 showed homogenous tissue distribution and excellent metabolic stability, which was unaffected by tissue oxygenation. PET studies in tumor bearing mice showed tumor-to-muscle ratios of 2.13±0.22 (n=4) at 2h after administration of β-[18F]1. In ex vivo autoradiography experiments β-[18F]1 distribution closely matched staining with the hypoxia marker pimonidazole. In conclusion, β-[18F]1 shows potential as PET hypoxia radiotracer which merits further investigation.
Biomedical Systems, AIT Austrian Institute of Technology GmbH, A-2444 Seibersdorf, Austria. Electronic address: thomas.wanek@ait.ac.at.
Thomas
T
Wanek
Biomedical Systems, AIT Austrian Institute of Technology GmbH, A-2444 Seibersdorf, Austria.
Katharina
K
Kreis
Institute of Organic Chemistry, University of Vienna, Währingerstraße 38, A-1090 Vienna, Austria.
Petra
P
Križková
Institute of Organic Chemistry, University of Vienna, Währingerstraße 38, A-1090 Vienna, Austria.
Anna
A
Schweifer
Institute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9/163, A-1060 Vienna, Austria.
Christoph
C
Denk
Biomedical Systems, AIT Austrian Institute of Technology GmbH, A-2444 Seibersdorf, Austria.
Johann
J
Stanek
Biomedical Systems, AIT Austrian Institute of Technology GmbH, A-2444 Seibersdorf, Austria.
Severin
S
Mairinger
Biomedical Systems, AIT Austrian Institute of Technology GmbH, A-2444 Seibersdorf, Austria.
Thomas
T
Filip
Biomedical Systems, AIT Austrian Institute of Technology GmbH, A-2444 Seibersdorf, Austria.
Michael
M
Sauberer
Biomedical Systems, AIT Austrian Institute of Technology GmbH, A-2444 Seibersdorf, Austria.
Patricia
P
Edelhofer
Biomedical Systems, AIT Austrian Institute of Technology GmbH, A-2444 Seibersdorf, Austria.
Alexander
A
Traxl
Biomedical Systems, AIT Austrian Institute of Technology GmbH, A-2444 Seibersdorf, Austria.
Viktoria E
VE
Muchitsch
Institute of Chemical Technologies and Analytics, Vienna University of Technology, Getreidemarkt 9/164, A-1060 Vienna, Austria.
Kurt
K
Mereiter
Institute of Organic Chemistry, University of Vienna, Währingerstraße 38, A-1090 Vienna, Austria.
Friedrich
F
Hammerschmidt
Department of Oncology, University of Alberta, Edmonton, Alberta, Canada.
Carol E
CE
Cass
Department of Oncology, University of Alberta, Edmonton, Alberta, Canada.
Vijaya L
VL
Damaraju
Biomedical Systems, AIT Austrian Institute of Technology GmbH, A-2444 Seibersdorf, Austria; Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria.
Oliver
O
Langer
Biomedical Systems, AIT Austrian Institute of Technology GmbH, A-2444 Seibersdorf, Austria.
Claudia
C
Kuntner
D000818:Animals; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D000860:Hypoxia / Q000000981:diagnostic imaging* / Q000473:pathology; D007093:Imidazoles / Q000032:analysis* / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051379:Mice; D015394:Molecular Structure; D009005:Monosaccharides / Q000032:analysis* / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000473:pathology; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000032:analysis* / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
C000621753:1-(6'-deoxy-6'-(18F)fluoro-beta-D-allofuranosyl)-2-nitroimidazole; D007093:Imidazoles; D009005:Monosaccharides; D019275:Radiopharmaceuticals
Azomycin nucleosides; PET; Pimonidazole; β-6′-[(18)F]FAZAL