Comparing hypoxia-targeting of 99mTc(CO)3-labeled 2-nitro 4-nitroimidazole

Non-invasive determination of hypoxia is an important problem in clinical nuclear medicine. Although (18)F-fluoromisonidazole is used clinically for hypoxia determination, the short half-life (t(1/2) = 109.77 min), high cost and less availability of cyclotrone-produced (18)F make (99m)Tc (t(1/2) = 6h)-based agents more desirable. With this aim, (99m)Tc(CO)(3)-labeled iminodiacetic acid derivatives of 2- and 4-nitroimidazole are investigated for their ability to target hypoxic tumors. A bifunctional chelating agent, N, N-bis[(tert-butoxycarbonyl)methyl]-2-bromoethylamine, was synthesized in the first step, which was then conjugated to the nitroimidazoles in the second step. The tert-butyl ester derivatives formed were hydrolyzed to obtain the iminodiacetic acid derivatives of corresponding nitroimidazoles. The radiolabeling of the iminodiacetic acid derivatives with [(99m)Tc(CO)(3)(H(2)O)(3)](+) core was carried out following a reported protocol. Biodistribution of the prepared complexes was carried out in Swiss mice bearing fibrosarcoma tumor. The 2-nitroimidazole complex showed a steady retention in activity (similar to 1.5% injected dose per gram [%ID/g]) in tumor throughout the period of study (3 h) indicating that it may be localized in the hypoxic cells. The 4-nitroimidazole counterpart, however, showed an initial uptake of similar to 4.6%ID/g at 30 min post injection, which was then observed to wash out rapidly.