bms-181321 and Hypoxia

A xanthate derivative (L) at the pendant hydroxy group of metronidazole, a nitroimidazole known to possess affinity for hypoxic tumors, has been used as the carrier molecule for targeted delivery of the gamma-emitting radioisotope 99mTc to tumors. The xanthate residues (S2(-)) from two molecules of this ligand (L) were used for chelation with the [99mTcN]2+ intermediate to form a square pyramidal and neutral [99mTcN/L2] complex in >95% yield using a low ligand concentration of 1 mg/mL (approximately 3 x 10(-3) M). Biodistribution studies carried out in Swiss mice bearing fibrosarcoma tumor showed selective accumulation of the injected activity in the tumor (1.44 +/- 0.26% per gram 1 h pi) with major clearance through hepatobiliary route. The complex showed high tumor/muscle ratio (2.15 and 3.35 at 1 and 3 h post-injection, respectively) and tumor/blood ratio, which were comparable to hypoxia targeting agents 99mTc-BMS181321 and 99mTc-BRU59-21 reported earlier.

Topics: Animals; Hypoxia; Imidazoles; Ligands; Metronidazole; Mice; Molecular Structure; Neoplasm Transplantation; Neoplasms, Experimental; Nitroimidazoles; Organotechnetium Compounds; Radionuclide Imaging; Radiopharmaceuticals; Structure-Activity Relationship; Time Factors; Tissue Distribution

It has been hypothesized that microvascular spasms cause cardiomyopathy. To elucidate the contribution of hypoxia to the development of cardiomyopathy, the newly-developed hypoxia tracer, Tc-99m nitroimidazole, was applied to detect myocardial hypoxia in a hamster model.. Tc-99m nitroimidazole (180 MBq) and I-125 iodoantipyrine (370 kBq) were injected into cardiomyopathic Syrian hamsters or control hamsters at age 10, 25, and 40 weeks (n = 6 in each group). The myocardial uptake of Tc-99m nitroimidazole was measured and dual tracer autoradiography was performed.. Histologic study revealed that the cardiomyopathic hamsters at age 10, 25 and 40 weeks were in the myocytolytic stage, the fibrotic and healing stage, and the hypertrophy and dilatation stage, respectively. Tc-99m nitroimidazole uptake was significantly greater in the cardiomyopathic hamsters than in the controls at age 25 weeks (cardiomyopathic hamsters, 33.3 +/- 4.7% g dose/g; control, 25.2 +/- 3.1), whereas there were no significant differences between both strains at age 10 and 40 weeks. The quantified concentration of I-125 iodoantipyrine in the cardiomyopathic hamster at age 40 weeks was significantly lower than that in the controls. When the Tc-99m nitroimidazole uptake was normalized by I-125 iodoantipyrine concentrations, the cardiomyopathic hamsters at age 25 and 40 weeks showed significantly greater uptake than the controls.. The myocardium in cardiomyopathic hamsters was hypoxic at the fibrotic and healing stage and may be hypoxic at the hypertrophy and dilatation stage. This may contribute to the development of cardiomyopathy.

Topics: Animals; Antipyrine; Autoradiography; Cardiomyopathy, Dilated; Cricetinae; Hypoxia; Iodine Radioisotopes; Mesocricetus; Myocardium; Nitroimidazoles; Organotechnetium Compounds

The purpose of the present study was to determine whether graded levels of low-flow ischemia would lead to graded differences in uptake and clearance of BMS181321. Using a perfused rat heart model, 7.4 MBq (200 microCi) of BMS181321 was infused over 20 min, followed by a 60-min clearance phase. Activity was monitored using an NaI detector. Four groups were studied using Krebs-Henseleit buffer perfusion using low flow or hypoxia: group 1=12 ml/min, group 2=3 ml/min, and group 3=1 ml/min during uptake and clearance phases, and group 4=12 ml/min with hypoxia during clearance. Control and low-flow groups were also perfused using red blood cells and albumin. There was a stepwise increase in peak myocardial uptake (% injected dose) as flow progressively decreased (group 1=2.4%+/-0.2% SEM, group 2=13.1%+/-0.7%, group 3=28.6%+/-2.4%, P <0.05). Group 3/group 1 mean peak activity ratio was 12:1. Mean 1-h fractional retention significantly increased in a stepwise manner as flow decreased (group 1=0.32+/-0.02, group 2=0.43+/-0.03, group 3=0.59+/-0.05, P <0.05). Group 3/group 1 mean 1-h clearance activity ratio was 30:1. Groups 5 and 6 perfused with red blood cells and albumin demonstrated similar increases in peak uptake and 1-h retention in the low-flow hearts. This study demonstrates a stepwise increase in uptake and a stepwise increase in retention rate of BMS181321 with progressive reduction in flow.

Topics: Animals; Hypoxia; Myocardial Ischemia; Myocardium; Nitroimidazoles; Organotechnetium Compounds; Rats; Technetium; Time Factors

Topics: Animals; Cardiomyopathies; Disease Models, Animal; Dogs; Hypoxia; Luminescent Measurements; Myocardial Ischemia; Myocardium; Nitroimidazoles; Organotechnetium Compounds; Oxygen; Radionuclide Imaging

Topics: Animals; Biomarkers; Dogs; Hypoxia; In Vitro Techniques; Myocardium; Nitroimidazoles; Organotechnetium Compounds; Oxygen Consumption; Rats; Rats, Sprague-Dawley

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.

Topics: Chromatography, High Pressure Liquid; Crystallization; Crystallography, X-Ray; Dimethylformamide; Electrochemistry; Hypoxia; Kinetics; Magnetic Resonance Spectroscopy; Molecular Structure; Nitroimidazoles; Organotechnetium Compounds; Radionuclide Imaging; Stereoisomerism; Xanthine Oxidase

A novel [99m]technetium-labeled nitroimidazole was preferentially taken up and retained by hypoxic cardiac muscle. In rat hearts perfused with O2 or N2 equilibrated cell-free medium, uptake of the infused nitroheterocycle and its subsequent washout displayed biphasic kinetics. For both uptake and washout, the early phase was very rapid whereas the late phase was much slower. The amount of radioactivity retained after 40 min of clearance was about two-fold greater in hypoxic hearts than in normoxic hearts. Cardiac myocytes and mitochondria isolated from rat heart also accumulated the nitroheterocycle. Association of the compound with heart cells was inversely related to the level of available oxygen and was independent of intracellular energy level or mitochondrial redox state in the presence of oxygen. The results indicate that this [99mTc]labeled nitroimidazole may serve as a sensitive marker of hypoxic myocardium.

Topics: Animals; Heart; Hypoxia; Male; Mitochondria, Heart; Molecular Structure; Myocardium; Nitroimidazoles; Organotechnetium Compounds; Radionuclide Imaging; Rats; Rats, Sprague-Dawley; Technetium