a New Radiopharmaceutical for Detecting TumorHypoxia

Fluorinated derivatives of etanidazole are being explored as probes for tumor hypoxia. Our research group has synthesized [18F]fluoroetanidazole (FETA)andnowreportsthe oxygen depen dencyof bindingto cellsin vitro,the biodistribution ofthe tracerin tumor-bearingmice and the analysis of metabolitesin their plasma and unne. Methods: Four cultured rodent cell lines (V79, 36B10, EMT6 and RIF1) were incubatedwith [18F]FETA for various times under graded 02 concentrations. We also corn paredthe biodistributionsof [18F]FETA and [18F]fluoromisonida zole (FMISO)at 2 and 4 h postinjectionin C3H mice bearing KHTntumors (130—430 mg). Reverse-phase high-pertormance liquidchromatography was usedto distinguishmetabolitesfrom parent drugs in urine and plasma of mice injected with [18F]FETA or [18F]FMISO. Results: In cells labeled in vitro, 02 levels of 6O0@-1 300ppminhibitedbindingby 50%relativeto uptakeunder anoxic conditions(<10 ppm).These inhibitoryvalues are not statisticallydifferentfrom those reportedfor [18F]FMISO in the same cell lines (700—1 500 ppm). In the biodistribution studies, uptake in heart, intestine, kidney and tumor was similar for both tracers 4 h after injection, whereas retention of [18F]FETA in liver andlungwassignificantlylower.Lessuptakeof[18F]FETA in liver suggests that this nitroimidazole is metabolized less than [18F]FMISO. The brain-to-blood ratiosindicatethat [18F]FETA readily crosses the blood-brain barrier. High-performance liquid chromatography of urinedemonstrated that10% of [18F]FETA derived activitywas in metabolites at 2 h postinjection, with 15% in metabolites by 4 h; comparable values for [18F]FMISOwere 36%and57%,respectively. ConclusIon: Weconclude from these data that [18F]FETA holds promise as a new hypoxiatracer in patients, having oxygen dependency of binding similar to [18F]FMISO invitroanddisplaying lessretention inliverandfewer