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Pharmacokinetics of [¹⁸F]FETNIM: A Potential Hypoxia Marker for PET

Medicity Research Laboratory and Radiopharmaceutical Chemistry Laboratory, Turku PET Centre, Turku; and Department of Oncology and Radiotherapy, Turku University Central Hospital, Turku, Finland

¹⁸F-labeled fluoroerythronitroimidazole (FETNIM) has been suggested as a marker of tumor hypoxia for use with PET. Our goal was to evaluate the pharmacokinetic properties of [¹⁸F]FETNIM in rats and analyze metabolites in human, dog, and rat plasma and urine. Metabolites in liver and tumor homogenates from tumor-bearing rats, as well as the biodistribution of the tracer, were also studied. Methods: Radio–thin-layer chromatography and digital autoradiography were used to distinguish metabolites from the parent drug in urine and plasma from 8 patients, 3 dogs, and 18 rats, as well as in liver and tumor homogenates from Sprague-Dawley rats bearing 7,12-dimethylbenzanthracene–induced rat mammary carcinoma. Biodistribution of [¹⁸F]FETNIM was also studied in rats at 15, 30, 60, 120, and 240 min after tracer injection. Results: Most of the radioactivity in plasma and urine was the unchanged tracer, whereas rat liver homogenates contained almost only metabolites of [¹⁸F]FETNIM. None of the species studied showed binding of tracer to plasma proteins. A large variation—3%–70%—in the radioactivity represented by unchanged [¹⁸F]FETNIM was found in rat tumor. A negative correlation was found between the percentage of radioactivity represented by unchanged [¹⁸F]FETNIM in tumor tissue and tumor uptake (percentage injected dose per gram of tissue) at later times. The highest radioactivity was seen in urine and kidney; the lowest uptake was in fat, cerebellum, and bone matrix. In contrast to matrix, bone marrow had high uptake of ¹⁸F. The tumor-to-blood ratio reached a maximum of 1.80 ± 0.64 at 2 h. Conclusion: We conclude that [¹⁸F]FETNIM shows low peripheral metabolism, little defluorination, and possible metabolic trapping in hypoxic tumor tissue. These suggest a potential use for this tracer in PET studies on hypoxia of cancer patients.

Key Words: [¹⁸F]fluoroerythronitroimidazole • hypoxia • metabolism • PET • biodistribution

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