• Journal of Radiopharmaceuticals and Molecular Probes
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• v.5 no.1
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• pp.18-25
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• 2019

2-Nitroimidazole derivatives have been reported to accumulate in hypoxic tissue. We prepared a novel $^{99m}Tc-MAG_3$-2-nitroimidazole and evaluated the feasibility for hypoxia imaging agent. $Bz-MAG_3$-2-nitroimidazole was synthesized by direct coupling of $Bz-MAG_3$ and 2-nitroimidazole using dicyclohexylcarbodiimide. $Bz-MAG_3$-2-nitroimidazole was labeled with $^{99m}Tc$ in the presence of tartaric acid and $SnCl_2-2H_2O$ at $100^{\circ}C$ for 30 min. And the reaction mixture was purified by $C_{18}$ Sep-pak cartridge. The labeling efficiency and the radiochemical purity were checked by ITLC-SG/acetonitrile. The tumor was grown in balb/c mice for 8~13 days after the subcutaneous injection of tumor cells, CT-26 (murine colon adenocarcinoma cell). Biodistribution study and tumor autoradiography were performed in the xenografted mice after i.v injection of 74 kBq/0.1 mL and 19 MBq/0.1 mL of $^{99m}Tc-MAG_3$-2-nitroimidazole, respectively. In vivo images of $^{99m}Tc-MAG_3$-2-nitroimidazole in tumor bearing mice were obtained 1.5 hr post injection. The labeling efficiency was $45{\pm}20%$ and the radiochemical purity after purification was over 95%. Paper electrophoresis confirmed negative charge of $^{99m}Tc-MAG_3$-2-nitroimidazole. $^{99m}Tc-MAG_3$-2-nitroimidazole was very stable at room temperature and its protein binding was 53%. The $^{99m}Tc-MAG_3$-2-nitroimidazole exhibited high uptake in the liver, stomach and intestine. In biodistribution study using tumor bearing mice, the uptakes (% ID/g) of the tumor were $0.5{\pm}0.1$, $0.4{\pm}0.0$, $0.2{\pm}0.1$ and $0.1{\pm}0.1$ at 5, 15, 30 min and 4 hrs. Tumor/muscle ratio were $1.4{\pm}0.1$, $2.2{\pm}0.83$, $3.0{\pm}0.9$, and 3.7 (n=2) for 5, 15, 30 min and 4 hrs. The uptake in hypoxic area was found higher than in non-hypoxic area of tumor tissue by autoradiography. In vivo images showed the relatively faint uptake to the hypoxic tumor region. $^{99m}Tc-MAG_3$-2-nitroimidazole was successfully synthesized and found feasible for imaging hypoxia.

• Journal of Radiopharmaceuticals and Molecular Probes
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• v.5 no.2
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• pp.101-112
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• 2019

Herein, 2-nitroimidazole-fluorophore conjugates were synthesized by linking 2-nitroimidazole and FITC or RITC via thiourea bonds. The prepared derivatives were stable for 2 h in Dulbecco's modified Eagle's medium (DMEM) at 37 ℃. The novel conjugates were studied for their in vitro uptake under hypoxic conditions using U87MG and CT-26 cell lines, showing significantly higher uptakes in hypoxic than normoxic cells. Immunohistochemical analysis confirmed hypoxia in U87MG and CT-26 xenografted tumor tissues. Moreover, the prepared conjugates were evaluated by in vivo experiments after intravenous injection in U87MG and CT-26 xenografted mice. Hypoxia was confirmed by immunohistochemistry of the prepared derivatives with co-injected pimonidazole. Confocal microscopy of the prepared derivatives showed strong fluorescence in hypoxic tumor tissues correlated with the pimonidazole distribution. This suggested that the 2-nitroimidazole-fluorophore conjugates are promising optical imaging probes for tumor hypoxia and are promising substitutes for pimonidazole immunohistochemistry, which requires a multi-step procedure of incubation involving antibody, second antibody, dye, hydrogen peroxide, and multiple washing steps.

• Korean Journal of Microbiology
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• v.14 no.4
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• pp.151-158
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• 1976

Using Ames'Salmonella/microsome system, mutagenicity of antirichomonal nitrofuran, nitroimidazole, and nitrothiazole derivatives was examined. Nitrofurantoin, nifuratel, furazolidone, metronidazole, nimorazole, ornidazole, and aminitrozole showed potent mutagenicity en $TA_100$ strain which is a base substitute mutant and contains R-factor plasmid pKM101 without microsomal enzyme activation. In addition, nifuratel, furazolidone, metronidazole, and ornidazole also induced frameshift mutation in $TA_98$ strain.

• Journal of Radiopharmaceuticals and Molecular Probes
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• v.2 no.2
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• pp.73-83
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• 2016

Imaging hypoxia using positron emission tomography (PET) is of great importance for cancer therapy. [$^{18}F$] Fluoromisonidazole (FMISO) was the first PET agent used for imaging tumor hypoxia. Various radiolabeled nitroimidazole derivatives such as [$^{18}F$]fluoroerythronitroimidazole (FETNIM), [$^{18}F$]1-${\alpha}$-D-(2-deoxy-2-fluoroarabinofuranosyl)-2-nitroimidazole(FAZA), 2-(2-nitroimidazol-1-yl)-N-(3,3,3-[18F]-trifluoropropyl)acetamide ([$^{18}F$]EF-3), [$^{18}F$]2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide (EF-5), 3-[$^{18}F$]fluoro-2-(4-((2-nitro-1H-imidazol-1-yl)methyl)-1H-1,2,3,-triazol-1-yl)-propan-1-ol ([$^{18}F$]HX-4), and [$^{18}F$]fluoroetanidazole (FETA) were developed successively. However, these imaging agents still produce PET images with limited resolution; the lower blood flow in hypoxic tumors compared to normoxic tumors results in low uptake of the agents in hypoxic tumors. Thus, the development of better imaging agents is necessary.

• The Korean Journal of Nuclear Medicine Technology
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• v.27 no.2
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• pp.83-93
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• 2023

Hypoxia indicates the condition of low oxygen levels in tissues. In oncology, hypoxia can induce cancer progression and metastasis, as well as cause resistance to cancer therapies. The detection of hypoxia by using molecular imaging, particularly, positron emission tomography (PET) has been extensively studied due to many advantages. Nitroimidazoles, the moieties that can be trapped in hypoxic tissues due to selective reduction, have been used to design and synthesize of hypoxia-targeting radiopharmaceuticals. This review provides a summary of synthetic routes towards ¹⁸F-labeled-nitroimidazole radiotracers for PET imaging of hypoxia.

• Archives of Pharmacal Research
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• v.26 no.10
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• pp.773-777
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• 2003

In this study, some new nitroimidazole derivatives were obtained from 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethylamine dihydrochloride (4) and 1-(2-bromoethyl)-2-methyl-5-nitroimidazole (5), which were prepared using metronidazole. Compound 4 was reacted with arylisothiocyanates (6) to obtain 1-[2-(2-methyl-5-nitroimidazol-1-yl)ethyl]-3-arylthioureas (7) and the latter with $\alpha$-bromoacetophenones (8) to give -3-[2-(2-methyl-5-nitroimidazol-1-yl)ethyl]-2-arylimino-4-aryl-4-thiazolines (9). Also 1-[2-(2-methyl-5-nitroimidazol-1-yl)ethyl]-2-phenyl-4-arylideneimidazolin-5-ones (11) were prepared by reaction of 4 with 2-phenyl-4-arylidene-5-oxazolones (10). The reaction of the other starting material 5 with 5-arylidenethiazolidin-2,4-dione (12) gave 3-[2-(2-methyl-5-nitroimidazol-1-yl)ethyl]-5-arylidenethiazolidin-2,4-dione (13) derivatives. Structural elucidation of the compounds was performed by IR, $^1H-NMR$ and MASS spectroscopic data and elemental analysis results. Antimicrobial activities of the compounds were examined and moderate activity was obtained.

• The Korean Journal of Nuclear Medicine
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• v.39 no.2
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• pp.141-145
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• 2005

Hypoxia (decreased tissue oxygen tension) is a component of many diseases such as tumors, cerebrovascular diseases and ischemic heart diseases. Although hypoxia can be secondary to a low inspired $pO_2$ or a variety of lung disorders, the most common cause is ischemia due to an oxygen demand greater than the local oxygen supply. In the heart tissue, hypoxia is often observed in persistent low-flow states, such as hibernating myocardium. Direct "hot spot" imaging of myocardial tissue hypoxia is potentially of great clinical importance because it may provide a means of identifying dysfunctional chronically ischemic but viable hibernating myocardium. A series of radiopharmaceuticals that incorporate nitroimidazole moieties have been synthesized to detect decreased local tissue pO2. In contrast to agents that localize in proportion to perfusion, these agents concentrate in hypoxic tissue. However, the ideal agents are not developed yet and the progress is very slow. Furthermore, the research focus is on tumor hypoxia nowadays. This review introduces the myocardial hypoxia imaging with summarizing the development of radiopharmaceuticals.

• Archives of Pharmacal Research
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• v.27 no.5
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• pp.502-506
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• 2004

Two series of 2-(5-nitro-2-furyl)- and 2-(1-methyl-5-nitro-1H-imidazol-2-yl)-5-propyl, allyl and propargyl)thio-1,3,4-thiadiazoles (6a-f) and 2-(5-nitro-2-furyl)- and 2-(1-methyl-5-nitro-1 H-imidazol-2-yl)-5-(nitrobenzyl)thio-1,3,4-thiadiazole derivatives (8a-f) have been synthesized and evaluated against Mycobacterium tuberculosis, as part of the TAACF TB screening program under direction of the US National Institute of Health, the NIAID division. Primary screening was conducted at a single concentration, 6.25 $\mu\textrm{g}$mL$^{-1}$ , against M. tuberculosis H$_{37}$ Rv in BACTEC 12B medium, using the Microplate Alamar Blue Assay (MABA). The minimum inhibitory concentration (MIC) was determined for the compounds that demonstrated $\geq$90% growth inhibition in the primary screening. A varying degree of antituberculosis activity (from 0-97% of growth inhibition) was observed with the alkylthio series (6a-f), and the nitroimidazole derivative with a propylthio group (6b) and the nitrofuran derivative with a propargylthio group (6e), were the most active compounds (MIC=3.13 and 1.56 /$\mu\textrm{g}$mL$^{-1}$ , respectively). Among the nitrobenzylthio derivatives (8a-f), all the ortho, meta and para nitrobenzyl isomers in the nitrofuran series exhibited good antituberculosis activity (MIC=3.13 $\mu\textrm{g}$mL$^{-1}$ ), while the corresponding nitroimidazole analogues were completely inactive (Inhibition=0%).

• Journal of Radiopharmaceuticals and Molecular Probes
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• v.1 no.2
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• pp.137-144
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• 2015

Hypoxia is an important adverse prognostic factor for tumor progression and is a major cause of failure of radiation therapy. In case of short-term hypoxia, the metabolism can recover to normal, but if hypoxia persists, it causes irreversible cell damage and finally leads to death. So a hypoxia marker would be very useful in oncology. In particular, 2-nitroimidazole can be reduced to form a reactive chemical species, which can bind irreversibly to cell components in the absence of sufficient oxygen, thus, the development of radiolabeled nitroimidazole derivatives for the imaging of hypoxia remains an active field of research to improve cancer therapy result. 2-nitroimidazole based hypoxia marker, [$^{18}F$]FMISO holds promise for the evaluation of tumor hypoxia by Positron emission tomography (PET), at both global and local levels. In the present study, [$^{18}F$]FMISO was synthesized using an automatic synthesis module with high radiochemical purity (>99%) in 60 min. Immunohistochemical analysis using pimonidazole confirmed the presence of hypoxia in xenografted CT-26 tumor tissue. A biodistribution study in CT-26 xenografted mice showed that the increased tumor-to-muscle ratio and tumor-to-blood ratios from 10 to 120 min post-injection. In the PET study, [$^{18}F$]FMISO also showed increased tumor-to-muscle ratios from 10 to 120 min post-injection. In conclusion, this study demonstrates the feasibility and utility of [$^{18}F$]FMISO for imaging hypoxiain mouse colon cancer model using small animal PET.

• Nuclear Medicine and Molecular Imaging
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• v.41 no.2
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• pp.91-96
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• 2007

The measurement of pathologically low levels of tissue $pO_2$ is an important diagnostic goal for determining the prognosis of many clinically important diseases including cardiovascular insufficiency, stroke and cancer. The target tissues nowaday have mostly been tumors or the myocardium, with less attention centered on the brain. Radiolabelled nitroimidazole or derivatives may be useful in identifying the hypoxic cells in cerebrovascular disease or traumatic brain injury, and hypoxic-ischemic encephalopathy. In acute stroke, the target of therapy is the severely hypoxic but salvageable tissue. $^{18}F-MISO$ PET and $^{99}mTc-EC-metronidazole$ SPECT in patients with acute ischemic stroke identified hypoxic tissues and ischemic penumbra, and predicted its outcome. A study using $^{123}I-IAZA$ in patient with closed head injury detected the hypoxic tissues after head injury. Up till now these radiopharmaceuticals have drawbacks due to its relatively low concentration with hypoxic tissues associated with/without low blood-brain barrier permeability and the necessity to wait a long time to achieve acceptable target to background ratios for imaging in acute ischemic stroke. It is needed to develop new hypoxic marker exhibiting more rapid localization in the hypoxic region in the brain. And then, the hypoxic brain imaging with imidazoles or non-imidazoles may be very useful in detecting the hypoxic tissues, determining therapeutic strategies and developing therapeutic drugs in several neurological disease, especially, in acute ischemic stroke.