In vitro and in vivo evaluation of [(18)F]F-GAZ, a novel oxygen-mimetic azomycin-glucose conjugate, for imaging hypoxic tumor.

Several F-18-labeled 2-nitroimidazole (azomycin) derivatives have been proposed for imaging hypoxia using positron emission tomography (PET). Their cell penetration is based on passive diffusion, which limits their intracellular concentration maxima. The purpose of this study was to investigate the uptake of N-(2-[F-18]fluoro-3-(6-O-glucosyl)propyl-azomycin ([F-18]F-GAZ), a new azomycin-glucose conjugate, in vitro and in vivo. [F-18]F-GAZ was synthesized from its tetraacetyl nosylate precursor by nucleophilic radiofluorination. [F-18]F-GAZ was evaluated in vivo in EMT-6 tumor-bearing Balb/C mice utilizing the PET and biodistribution analysis. In vitro uptake of [F-18]FDG by EMT-6 cells was measured in the presence of unlabeled F-GAZ, 2-FDG, and D-glucose. [F-18]F-GAZ was rapidly cleared from all tissues, including the blood pool and kidneys, with ultimate accumulation in the urinary bladder. Uptake of tracer doses of [F-18]F-GAZ into EMT-6 tumors was fast, reaching a standardized uptake value of 0.66+/-0.05 within 5-6 minutes postinjection (p.i.), and decreased to 0.24+/-0.04 by 60 minutes p.i. (n = 6). A tumor-muscle ratio of 1.87+/-0.18 was observed after 60 minutes. Total uptake of [F-18]F-GAZ in tumors (60 minutes) amounted to 1.25%+/-0.15% ID/g versus 0.61%+/-0.14% ID/g (n = 4) in muscle. Similar biodistribution and excretion were observed using carrier-added (100 mg/kg) doses of F-GAZ. In vitro, D-glucose and unlabeled 2-FDG were two orders of magnitude more potent than F-GAZ as competitive inhibitors of [F-18]FDG uptake into EMT-6 cells. Besides its interaction with glucose transporters, F-GAZ seems to be not transported in the presence of glucose. Furthermore, [F-18]F-GAZ is unlikely to be effective as a hypoxia imaging agent. The low in vivo toxicity and substantial retention in tumor observed at high doses of F-GAZ do provide rationale for further testing as a radiosensitizer for external beam radiation therapy of radioresistant, hypoxic tumors.