In Vivo Ester Hydrolysis as a New Approach in Development of Positron Emission Tomography Tracers for Imaging Hypoxia.

Hypoxia is an important biochemical and physiological condition associated with uncontrolled growth of tumor. Measurement of hypoxia in tumor tissue may be useful in characterization of tumor progression and monitoring drug treatment. [¹⁸F]FMISO is the most widely employed radiotracer for imaging of hypoxic tissue with positron emission tomography (PET). However, it showed relatively low uptake in hypoxic tissues, which led to low target-to-background contrast in PET images. To overcome these shortcomings, two novel 2-fluoroproprioic acid esters, nitroimidazole derivatives 2-fluoropropionic acid 2-(2-nitro-imidazol-1-yl)-ethyl ester (FNPFT, [¹⁹F]5) and 2-fluoropropionic acid 2-(2-methyl-5-nitro-imidazol-1-yl)-ethyl ester (FMNPFT, [¹⁹F]8), were prepared and tested. Radiolabeling of [¹⁸F]5 and [¹⁸F]8 was accomplished in 45 min (radiochemical purity >95%, the decay-corrected radiochemical yield of [¹⁸F]5 was 11 ± 2%, and that of [¹⁸F]8 was 13 ± 2%, n = 5). In vitro cell uptake studies using EMT-6 tumor cells showed that both radiotracers [¹⁸F]5 and [¹⁸F]8 displayed significantly higher uptake in hypoxic cells than those under normoxic condition, while 2-[¹⁸F]fluoropropionic acid (2-[¹⁸F]FPA) displayed no difference. Biodistribution studies in mice bearing EMT-6 tumor showed that [¹⁸F]5, [¹⁸F]8, and 2-[¹⁸F]FPA displayed similar tumor and major organ uptakes. Tumor uptake values for all three agents were higher than those of [¹⁸F]FMISO, respectively ( P < 0.05). This is likely due to a rapid in vivo hydrolysis of [¹⁸F]5 and [¹⁸F]8 to their metabolite, 2-[¹⁸F]FPA. Micro PET imaging studies in the same EMT-6 implanted mice tumor model also demonstrated that both [¹⁸F]5 and [¹⁸F]8 displayed similar tumor uptake comparable to that of 2-[¹⁸F]FPA. In conclusion, two new fluorine-18 labeled nitroimidazole derivatives, [¹⁸F]5 and [¹⁸F]8, showed good tumor uptakes in mice bearing EMT-6 tumor. However, in vivo biodistribution results suggested that they were more likely reflect the predominance of in vivo produced metabolite, 2-[¹⁸F]FPA, which may not be related to tumor hypoxic condition.