[F-18]-EF5, a marker for PET detection of hypoxia: synthesis of precursor and a new fluorination procedure

There is a great deal of clinical and experimental interest in determining tissue hypoxia using non-invasive imaging methods. We have developed EF5, 2 -(2-nitro-1[H]-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)-acetamide, wi th both invasive and non-invasive hypoxia detection in mind. EF5 and other 2-nitroimidazoles are used to detect hypoxia, because the rate of their bio reductive metabolism is inversely dependent on oxygen partial pressure. Suc h metabolism leads to the formation of covalent adducts within the metaboli zing cells. Previously, we have described the invasive detection of these a dducts by highly specific monoclonal antibodies after tissue biopsy. In thi s report, we demonstrate the synthesis of F-18-labeled EF5, [F-18]-2-(2-nit ro-1 [H]-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)-acetamide, in great er than 10% yield by direct fluorination of the newly synthesized precursor 2-(2-nitro-1[H]-imidazol-1-yl)- N-(2,3,3-trifluoroallyl)-acetamide by [F-1 8]-F-2 in trifluoroacetic acid. Our objective was to optimize the electroph ilic fluorination of the fluorinated alkene bond with fluorine gas, a new m ethod of F-18-labeling of polyfluorinated molecules. Previous biodistributi on studies in mice have demonstrated uniform access of EF5 to all tissues w ith bioelimination dominated by renal excretion. When [F-18]-EF5 was inject ed into a rat followed by urine collection and analysis, we found no detect able metabolism to other radioactive compounds. Thus, [F-18]-EF5 should be well suited for use as a non-invasive hypoxia marker with detection using p ositron emission tomography (PET). (C) 2000 Elsevier Science Ltd. All right s reserved.