TCO(PNAO-1-(2-NITROIMIDAZOLE)) [BMS-181321], A NEW TECHNETIUM-CONTAINING NITROIMIDAZOLE COMPLEX FOR IMAGING HYPOXIA - SYNTHESIS, CHARACTERIZATION, AND XANTHINE OXIDASE-CATALYZED REDUCTION

A technetium(V)oxo nitroimidazole complex that shows promise for imagi ng 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-contain ing derivative of propyleneamine oxime (PnAO). The Tc-99 complex [Tc-9 9] Oxo[[3,3,9,9-tetramethyl-1-(2-nitro- 1H-imidazol-1-yl)-4,8-diazaund ecane-2,10-dione dioximato]-(3-)-N,N',N'',N'''] technetium (V) was syn thesized both from pertechnetate and [TcO(Eg)(2)](-)(Eg = ethylene gly col). A new synthetic route to TcO(PnAO) (2) is also described. (TcO)- Tc-99(PnAO-1-(2-nitroimidazole)) was characterized by H-1 NMR, IR, and UV/vis spectroscopy, HPLC, FAB mass spectrometry, and X-ray crystallo graphy. Electrochemistry of 1 reveals that the nitro redox chemistry f ound in the ligand is maintained upon coordination to technetium but s hifts to a slightly more positive potential. Using chiral HPLC (Chirac el OD), Tc-99m (1) was resolved into its two enantiomers. However, the two isomers were found to racemize quickly (t(1/2) < 2 min) in the pr esence of water. Localization of 1 is believed to be mediated by enzym atically catalyzed reduction of the nitroimidazole group, so the in vi tro reaction of Tc-99(l) with the nitroreductase enzyme xanthine oxida se (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-con taining complex (2). The rate of reduction of the Tc-nitroimidazole co mplex (1.5 +/- 0.16 nmol/min per unit XOD) was faster than that observ ed previously for the nitroimidazole BATOs (BATO = boronic acid adduct of technetium dioxime) and was about two-thirds that of fluoromisonid azole, a compound that has proven useful for imaging hypoxia in humans when labeled with F-18, These data suggest that BMS-181321 (1) has th e potential to be recognized by nitroreductase enzymes in vivo, thus s atisfying one of the criteria required for this potential hypoxia imag ing agent.