Tumor cells exhibiting reduced oxygen concentration (hypoxia) are heterogeneously distributed in solid tumors and are associated with increased aggressiveness, ability to metastasize, and resistance to therapeutic intervention. Currently, nitroimidazoles labeled with [18F]fluorine are the standard hypoxia-sensitive imaging probes for use in positron emission tomography (PET). For all current hypoxia PET imaging agents, such as [18F]FMISO (Figure 1, left), reactive nitroimidazole intermediates remain covalently bound to [18F]fluorine and form conjugates with nucleophilic biomolecules. Diffusion and circulation of these radioactive metabolites causes significant non-tumor tissue accumulation and delays clearance, resulting in low signal-to-noise ratios and limited clinical utility. We propose a novel “trigger and release” strategy (Figure 1, right) for imaging tumor hypoxia in vivo. Hypoxia-specific bioreduction of a nitroaromatic “trigger” induces destruction of a self-immolative linker and release a [18F]fluorine-labeled effector. The [18F]fluorine-labeled payload remains trapped within hypoxic tumor cells, and imaging is not confounded by the fate of the unlabeled “trigger” moiety. A library of tracer candidates has been synthesized, and mechanistic proof-of-principle was demonstrated using a bacterial nitroreductase (E. coli NfsA). Several tracer candidates were radiolabeled with [18F]fluorine, and compared to [18F]FMISO in PET imaging studies of mice bearing bilateral subcutaneous A549 xenograft tumors.

Novel "trigger and release" strategy for imaging tumor hypoxia in vivo

251st National Meeting (2016)

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