A
technetium(V)oxo
nitroimidazole complex that shows promise for imaging regional
hypoxia in vivo, [
BMS-181321, TcO(PnAO-1-(2-
nitroimidazole))] (1) was prepared from 3,3,9,9-tetramethyl-1-(2-nitro-1H-imidazol-1-yl)-4,8-diazaundecane -2,10-dione dioxime, a 2-nitroimidazole-containing derivative of propyleneamine
oxime (PnAO). The 99Tc complex [99Tc]Oxo[[3,3,9,9-tetramethyl-1-(2-nitro-1H-imidazol-1-yl)-4,8- diazaundecane-2,10-dione dioximato]-(3-)-N,N',N'',N''']
technetium (V) was synthesized both from
pertechnetate and [TcO(Eg)2]- (Eg =
ethylene glycol). A new synthetic route to TcO(PnAO) (2) is also described. 99TcO(PnAO-1-(2-nitroimidazole)) was characterized by 1H NMR, IR, and UV/vis spectroscopy, HPLC, FAB mass spectrometry, and X-ray crystallography. Electrochemistry of 1 reveals that the nitro redox chemistry found in the
ligand is maintained upon coordination to
technetium but shifts to a slightly more positive potential. Using chiral HPLC (Chiracel OD), 99mTc (1) was resolved into its two enantiomers. However, the two isomers were found to racemize quickly (t1/2 < 2 min) in the presence of water. Localization of 1 is believed to be mediated by enzymatically catalyzed reduction of the
nitroimidazole group, so the in vitro reaction of 99Tc(1) with the
nitroreductase enzyme xanthine oxidase (XOD) was studied. XOD catalyzed the quantitative reduction of the
nitroimidazole group on the molecule under anaerobic conditions in the presence of
hypoxanthine. No reaction was noted using a non-nitro-containing complex (2). The rate of reduction of the Tc-
nitroimidazole complex (1.5 +/- 0.16 nmol/min per unit XOD) was faster than that observed previously for the
nitroimidazole BATOs (BATO =
boronic acid adduct of
technetium dioxime) and was about two-thirds that of
fluoromisonidazole, a compound that has proven useful for imaging
hypoxia in humans when labeled with 18F. These data suggest that BMS-181321 (1) has the potential to be recognized by
nitroreductase enzymes in vivo, thus satisfying one of the criteria required for this potential
hypoxia imaging agent.