2-(2-Nitro-1 H-imidazol-1-yl)- N-(2,2,3,3,3-[18F]pentafluoropropyl)-acetamide

Excerpt

Hypoxia in malignant tumors is thought to be a major factor limiting the efficacy of chemotherapy and radiotherapy, and its accurate diagnosis is considered a very important and urgent problem to address. This has led to the search for and development of hypoxia-targeted imaging techniques and non-invasive markers of tumor hypoxia. Among those, ¹⁸F-labeled nitroimidazoles - used in conjunction with positron emission tomography (PET) – offer a alternative that is less invasive and less prone to sampling errors than the Eppendorf (oxygen) electrode method (1, 2).

Fluoromisonidazole ([¹⁸F]FMISO) is the nitroimidazole derivative most widely used with PET. Novel 2-nitroimidazoles, such as ¹⁸F-labeled fluoroetanidazole ([¹⁸F]FETA) (3), fluoroerythronitroimidazole ([¹⁸F]FETNIM) (4), 4-bromo-1-(3-fluoropropyl)-2-nitroimidazole (4-Br[¹⁸F]FPN) (5), and 2-(2-nitroimidazol-1H-yl)-N-(3-fluoropropyl)acetamide ([¹⁸F]EF1) (6), are currently under investigation as PET markers for hypoxia.

The pentafluorinated molecule EF5 (2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)-acetamide), previously used for measurement of hypoxia by immunohistochemistry (7) and flow cytometry (8), is currently being investigated as a PET agent for hypoxia. [¹⁸F]EF5 has the advantage of being more lipophilic than [¹⁸F]EF1 (octanol-water partition coefficient of 5.7 for [¹⁸F]EF5 versus 0.35 for [¹⁸F]EF1) because of its multiple fluorine atoms. [¹⁸F]EF5 can easily access all tissues, including those in the nervous system.

The oxygen-dependent metabolism of [¹⁸F]EF5 is an intracellular process consisting of a series of one-electron reductions. The nitro-radical anion produced in the first reduction step is very reactive toward oxygen, leaving no substrate for the second step of the reduction process. In contrast, a low-oxygen environment induces further reductive reactions that ultimately lead either to the formation of reactive products that can covalently bind to cell components or to charged species that diffuse slowly out of the tissues (1). The reactive products observed during this multistep process include nitroso (2e^-), hydroxylamine (4e^-), and amine (6e^-) derivatives. When fragmentation of the imidazole ring occurs, reactive portions of the molecule, such as glyoxal, bind to macromolecular components of cells in tissues and tumors (2).