Linder K E, Chan Y W, Cyr J E, Malley M F, Nowotnik D P, Nunn A D
Bristol-Myers Squibb Pharmaceutical Research Institute, Lawrenceville, New Jersey 08543-4000.
J Med Chem. 1994 Jan 7;37(1):9-17. doi: 10.1021/jm00027a002.
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.
一种有望用于体内区域性缺氧成像的锝（V）氧代硝基咪唑配合物[BMS - 181321，TcO(PnAO - 1-(2 - 硝基咪唑))]（1），由3,3,9,9 - 四甲基 - 1-(2 - 硝基 - 1H - 咪唑 - 1 - 基)-4,8 - 二氮杂十一烷 - 2,10 - 二酮二肟制备而成，它是丙烯胺肟（PnAO）的一种含2 - 硝基咪唑的衍生物。99Tc配合物[99Tc]氧代[[3,3,9,9 - 四甲基 - 1-(2 - 硝基 - 1H - 咪唑 - 1 - 基)-4,8 - 二氮杂十一烷 - 2,10 - 二酮二肟基]-(3 - ) - N,N',N'',N''']锝（V）既可以由高锝酸盐合成，也可以由[TcO(Eg)2]-（Eg = 乙二醇）合成。还描述了一种合成TcO(PnAO)（2）的新路线。99TcO(PnAO - 1-(2 - 硝基咪唑))通过1H NMR、IR、UV/vis光谱、HPLC、FAB质谱和X射线晶体学进行了表征。配合物1的电化学性质表明，配体中发现的硝基氧化还原化学在与锝配位后得以保持，但电位略有正移。使用手性HPLC（Chiracel OD），99mTc（1）被拆分为其两种对映体。然而，发现这两种异构体在有水存在的情况下会迅速外消旋（t1/2 < 2分钟）。据信，配合物（配合物1）的定位是由硝基咪唑基团的酶促催化还原介导的，因此研究了99Tc(1)与硝基还原酶黄嘌呤氧化酶（XOD）的体外反应。在次黄嘌呤存在的厌氧条件下，XOD催化分子上硝基咪唑基团的定量还原。使用不含硝基的配合物（配合物2）时未观察到反应。Tc - 硝基咪唑配合物的还原速率（每单位XOD为1.5±0.16 nmol/分钟）比之前观察到的硝基咪唑BATOs（BATO = 锝二肟硼酸加合物）的还原速率快，约为氟米索硝唑还原速率的三分之二，氟米索硝唑在用18F标记时已被证明可用于人体缺氧成像。这些数据表明，BMS - 181321（1）在体内有可能被硝基还原酶识别，从而满足这种潜在的缺氧成像剂所需的一个标准。
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