Preparation and bioevaluation of a novel Tc-labelled propylene amine oxime (PnAO) containing two 4-methyl-2-nitroimidazole groups as a promising tumor hypoxia imaging agent.

Hypoxia is a common phenomenon in solid tumors, and its presence inhibits the efficacy of tumor chemotherapy and radiotherapy. Accurate measurement of hypoxia before tumor treatment is essential. Three propylene amine oxime (PnAO) derivatives with different substituents attached to 2-nitroimidazole were synthesized in the work, they are 3,3,9,9-tetramethyl-1,11-bis(4-bromo-2-nitro-1H-imidazol-1-yl)-4,8-diazaundecane-2,10-dione dioxime (Br2P2), 3,3,9,9-tetramethyl-1,11-bis(4-methyl-2-nitro-1H-imidazol-1-yl)-4,8-diazaundecane-2,10-dione dioxime (Me2P2) and 3,3,9,9-tetramethyl-1,11-bis(4,5-dimethyl-2-nitro-1H-imidazol-1-yl)-4,8-diazaundecane-2,10-dione dioxime (2Me2P2).

Improving tumor/muscle and tumor/blood ratios of Tc-labeled nitroimidazole propylene amine oxime (PnAO) complexes with ethylene glycol linkers.

Three nitroimidazole propylene amine oxime (PnAO) derivatives with different lengths of ethylene glycol chain were synthesized and radiolabeled with Tc. The radiochemical purities of three Tc-labeled complexes, oxo[[6,6,12,12-tetramethyl-1,17-bis(2-nitro-1H-imidazol-1-yl)-3,15-dioxa-7,11-diazaheptadecane-5, 13-dione dioximato] (3-)-N,N',N'',N''']-technetium-99m (Tc-2P2O1), oxo[[9,9,15,15-tetramethyl-1,23-bis(2-nitro-1H-imidazol-1-yl)-3,6,18,21-tetraoxa-10, 14-diazatricosane-8,16-dione dioximato] (3-)-N,N',N'',N''']-technetium-99m (Tc-2P2O2) and oxo[[15,15,21,21-tetramethyl-1,35-bis(2-nitro-1H-imidazol-1-yl)-3,6,9,12,24,27,30,33-octaoxa-16,20-diazapentatriacontane-14,22-dione dioximato] (3-)-N,N',N'',N''']-technetium-99m (Tc-2P2O4), were above 90%, and they were all stable both in vitro and in vivo. The hypoxia/normoxia uptake ratios of the three complexes were 2.

Synthesis and bioevaluation of the cyclopentadienyl tricarbonyl technetium-99m 2-nitroimidazole derivatives for tumor hypoxia imaging.

Hypoxia imaging agents can play an important role in the tumor treatment by avoiding the worse effect of radiotherapy and chemotherapy due to the tumor hypoxia. Due to the small size and easy coordination, tricarbonyl technetium-99m can be used to label a wide range of imaging agents. In this work, the tricarbonyl Tc labeled small-sized hypoxia imaging agents containing 2-nitroimidazoles were prepared, which have different carbon chain lengths between cyclopentadienyl and 2-nitroimidazole, and which have one or two 2-nitroimidazole groups.

Direct dissolution of UO in carboxyl-functionalized ionic liquids in the presence or absence of Fe-containing ionic liquids.

Dissolution of UO is a prerequisite for the reprocessing of spent nuclear fuel. This study showed that UO could be directly dissolved in a single carboxyl-functionalized ionic liquid (IL), [HOOCMmim][TfN] 1-carboxymethyl-3-methylimidazolium bistriflimide, or [HOOCEtmim][TfN] 1-carboxyethyl-3-methylimidazolium bistriflimide. The addition of an extra Fe-containing IL, [Emim][FeCl] (Emim, 1-ethyl-3-methylimidazolium) or [Bmim][FeCl] (Bmim, 1-butyl-3-methylimidazolium) could significantly improve the dissolution kinetics.

Synthesis and bioevaluation of radioiodinated nitroimidazole hypoxia imaging agents by one-pot click reaction.

Eight radioiodinated 2-nitroimidazole derivatives for use as hypoxia imaging agents were synthesized by one-pot click reaction using four azides, two alkynes, and [I]iodide ions and evaluated by hypoxic cellular uptake and biodistribution experiments. The results suggested that radiotracers with suitable partition coefficients (log P: -0.2-1.

Quaternary phosphonium modified cellulose microsphere adsorbent for Tc decontamination with ultra-high selectivity.

Decontamination of radioactive TcO from nuclear wastes is increasingly crucial for spent nuclear fuel reprocessing and environmental remediation. In the presence of a large excess of competitive anions, the selective separation of TcO is a major challenge for adsorbents. Herein, by using pre-radiation induced grafting polymerization, we have modified economical and environmentally friendly cellulose microspheres to obtain quaternary phosphonium decorated TcO adsorbents with an ultra-high selectivity, designated CMS-g-VBPPhNO.

Ionic liquids with polychloride anions as effective oxidants for the dissolution of UO.

Herein, polychloride ([Cl] or/and [Cl]) ionic liquids (ILs) were prepared from their imidazolium chloride precursors by the addition of chlorine gas. The highest storage ability of Cl was found in the [Bmim]Cl IL among the six imidazolium chlorides [Rmim]Cl (Rmim = Emim, 1-ethyl-3-methylimidazolium; Bmim, 1-butyl-3-methylimidazolium; Pmim, 1-propyl-3-methylimidazolium; Pnmim, 1-pentyl-3-methylimidazolium; Hmim, 1-hexyl-3-methylimidazolium; and Omim, 1-octyl-3-methylimidazolium). When a mixed IL of [Bmim][TfN] (1-butyl-3-methylimidazolium bistriflimide) and [Bmim]Cl was used, the IL cation could maintain good stability during the chlorination process, and the imidazolium cation [Bmim] could retain almost the same structure after the chlorine gas was introduced into the mixed IL according to H NMR spectroscopy.

A pre-targeting strategy for imaging glucose metabolism using technetium-99m labelled dibenzocyclooctyne derivative.

During the last four decades, nuclear medicine has undergone enormous growth, and positron emission tomography (PET) has been in the driving seat for most of the time. F-fluorodeoxyglucose (F-FDG) is the most widely used agent for the detection of hibernating myocardium and metabolically active cancer tissue. But its cost and limited availability are the main limitations.

Synthesis and Bioevaluation of Novel [F]FDG-Conjugated 2-Nitroimidazole Derivatives for Tumor Hypoxia Imaging.

Hypoxia imaging can guide tumor treatment and monitor changes in hypoxia during treatment. However, there is still no ideal hypoxia imaging agent for clinical applications. In this study, two novel 2-nitromidazole derivatives were synthesized and directly radiolabeled by [F]FDG in high radiochemical yield and excellent radiochemical purity.

A two-step strategy to radiolabel choline phospholipids with Tc in S180 cell membranes via strain-promoted cyclooctyne-azide cycloaddition reaction.

As tumor markers, the radiolabeling of choline (Cho)-containing phospholipids in cellular membranes with Tc is a challenge. The conventional strategy to combine the metallic radionuclide with Cho by large ligand damages the bioactivity of Cho, resulting in low tumor-to-nontumor ratios. Pretargeting strategy based on strain-promoted cyclooctyne-azide cycloaddition (SPAAC) reaction was applied to solve this general problem.

Fullerene/photosensitizer nanovesicles as highly efficient and clearable phototheranostics with enhanced tumor accumulation for cancer therapy.

A novel phototheranostic platform based on tri-malonate derivative of fullerene C70 (TFC70)/photosensitizer (Chlorin e6, Ce6) nanovesicles (FCNVs) has been developed for effective tumor imaging and treatment. The FCNVs were prepared from amphiphilic TFC70-oligo ethylene glycol -Ce6 molecules. The developed FCNVs possessed the following advantages: (i) high loading efficiency of Ce6 (up to ∼57 wt%); (ii) efficient absorption in near-infrared light region; (iii) enhanced cellular uptake efficiency of Ce6 in vitro and in vivo; (iv) good biocompatibility and total clearance out from the body.

Synthesis and radiolabeling of (64)Cu-labeled 2-nitroimidazole derivative (64)Cu-BMS2P2 for hypoxia imaging.

The objective of this study was to develop a positron emission tomography (PET) probe with hypoxia targeting specificity and a relatively long half-life. The synthesis, (64)Cu-labeling in vitro and in vivo study of the novel 2-nitroimidazole complex (64)Cu-BMS2P2 is presented in this study. The hypoxia targeting capacity of (64)Cu-BMS2P2 in vitro was evaluated and compared with the (64)Cu-BMS181321, and confirmed by PET imaging in vivo and immunohistochemistry for carbonic anhydrase 9 (CA9) in a tumor mouse model.

In vitro and in vivo evaluation of technetium-99m-labeled propylene amine oxime complexes containing nitroimidazole and nitrotriazole groups as hypoxia markers.

Hypoxia markers have been the subject of intensive research in radiopharmaceuticals, but there is little work on markers with multi-redox centers. It is necessary to further develop and investigate the compounds containing multi-redox centers systematically. Two propylene amine oxime ligands, compound 1, containing 3-nitro-1,2,4-triazole and 4-nitroimidazole and compound 2, containing 3-nitro-1,2,4-triazole and 2-nitroimidazole were synthesized and radiolabeled with (99m) Tc; then these complexes were also evaluated in vitro and in vivo.

Radioactive lutetium metallofullerene LuLuN@C-PCBPEG derivative: a potential tumor-targeted theranostic agent.

A radioactive metallofullerene LuLuN@C was firstly synthesized by means of neutron irradiation on LuN@C. After modification by methoxypolyethylene glycol amine, in vivo investigation on tumor-bearing mice was performed. The results reveal favorable affinity toward tumors, suggesting that the obtained LuLuN@C-PCBPEG could be promising for tumor diagnosis and therapy.

In vivo click reaction between Tc-99m-labeled azadibenzocyclooctyne-MAMA and 2-nitroimidazole-azide for tumor hypoxia targeting.

The bioactivity of nitroimidazole in Tc-99m-labeled 2-nitroimidazole, a traditional solid tumor hypoxia-imaging agent for single photon emission computed tomography (SPECT), is reduced by the presence of large ligand and metallic radionuclide, exhibiting lower tumor-to-nontumor ratios. In an effort to solve this general problem, a pretargeting strategy based on click chemistry (strain-promoted cyclooctyne-azide cycloaddition) was applied. The functional click synthons were synthesized as pretargeting components: an azide group linked to 2-nitroimidazole (2NIM-Az) serves for tumor hypoxia-targeting and azadibenzocyclooctyne conjugated with monoamine monoamide dithiol ligand (AM) functions as radiolabeling and binding group to azides in vivo.

Preparation and biological evaluation of ⁹⁹mTc-N4IPA for single photon emission computerized tomography imaging of hypoxia in mouse tumor.

In order to develop technetium-99m labeled nitroimidazole imaging agent for hypoxia in tumor, we have synthesized (99m)Tc-1-(4-nitroimidazole-yl)-propanhydroxyiminoamide, (99m)Tc-N4IPA complex, in high radiochemical purity and radiochemical yield. The biological evaluation of this complex includes the in vitro/vivo stability, cell uptake and Single Photon Emission Computerized Tomography (SPECT) imaging in mouse tumor models, respectively. These results demonstrate that (99m)Tc-N4IPA may have potential as clinical hypoxia imaging agent.

Fe-containing ionic liquids as effective and recoverable oxidants for dissolution of UO2 in the presence of imidazolium chlorides.

Imidazolium-based Fe-containing ionic liquids (ILs) can directly dissolve UO2 in the presence of their corresponding imidazolium chlorides without additional oxidants. The dissolution process follows pseudo first-order kinetics initially. Raman spectroscopic studies indicate that FeCl4(2-) is the predominant reduction product after UO2 dissolution, and attenuated total reflection-Fourier transform infrared spectroscopy indicates that the UO2(2+) complex is the principal product in the ILs.

A 2:1 dicationic complex of tetraethyl methylenebisphosphonate with uranyl ion in acetonitrile and ionic liquids.

A new 2:1 dicationic complex formed by TEMBP with uranyl ion in acetonitrile and two hydrophobic ILs, [BMIm][NTf(2)] and [N(4111)][NTf(2)], has been identified with combination of optical spectroscopic and mass spectrometric studies. With excess of TEMBP ligand (L/U > 2.0), the uranyl is completely coordinated by two ligands to form a dicationic complex [UO(2)(TEMBP)(2)](2+).

⁹⁹mTc/Re complexes bearing bisnitroimidazole or mononitroimidazole as potential bioreductive markers for tumor: synthesis, physicochemical characterization and biological evaluation.

Four monoamine-monoamide dithiol (MAMA) ligands containing two or one nitroimidazole moieties were synthesized and labeled with (99m)Tc (labeling yield > 95%). The proposed structures of (99m)Tc-complexes are identified by comparison with analogous Re-MAMA complexes. (99m)Tc-MAMA complexes show better physicochemical characters than (99m)TcO-(PnAO-1-(2-nitroimidazole)).

Synthesis, radiolabeling and biological evaluation of propylene amine oxime complexes containing nitrotriazoles as hypoxia markers.

Two propylene amine oxime (PnAO) complexes, 1, containing a 3-nitro-1,2,4-triazole and 2, containing two 3-nitro-1,2,4-triazoles, were synthesized and radiolabeled with (99m)Tc in high labeling yields. Cellular uptakes of (99m)Tc-1 and (99m)Tc-2 were tested using a S180 cells line. Under anoxic conditions, the cellular uptakes of (99m)Tc-1 and (99m)Tc-2 were 33.

Recent advances on radionuclide labeled hypoxia-imaging agents.

Hypoxic tissue exists in most of the solid tumors and hypoxia is a common character of these tumors. The existence of hypoxic tissue in the tumor decreases the efficacy of radiotherapy and chemotherapy. Radiolabeled hypoxia markers have been developed to measure the hypoxic tissue together with non-invasive imaging techniques such as PET, SPECT, and PET/CT.

Synthesis, radiolabeling, biodistribution and fluorescent imaging of histidine-coupled hematoporphyrin.

Introduction: Hematoporphyrin (Hp) and hematoporphyrin derivatives (HpDs) have been widely used as photosensitizers in photodynamic therapy (PDT). Radiolabeling of HpDs is helpful for preclinical and clinical studies of PDT.

Methods: The histidine-coupled hematoporphyrin (His-Hp) was synthesized and radiolabeled with [(99m)Tc(CO)(3)(H(2)O)(3)](+).

Effect of a second nitroimidazole redox centre on the accumulation of a hypoxia marker: synthesis and in vitro evaluation of 99mTc-labeled bisnitroimidazole propylene amine oxime complexes.

Up to now, most of the hypoxia markers contain only one nitroimidazole redox centre, such as 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 ((99m)Tc-1, BMS181321). Introducing a second nitroimidazole redox centre may enhance the hypoxic accumulation of the markers. In the present work, four (99m)Tc-1 (BMS181321, containing one 2-nitroimidazole) analogues, that is, (99m)Tc-2 (containing two 2-nitroimidazoles), (99m)Tc-3 (containing one 4-nitroimidazole), (99m)Tc-4 (containing two 4-nitroimidazoles) and (99m)Tc-5 (containing both a 2-nitroimidazole and a 4-nitroimidazole) were synthesized, and the hypoxic accumulation was evaluated in vitro using murine sarcoma S180 cells.

Preliminary studies of 99mTc-BnAO and its analogues: synthesis, radiolabeling and in vitro cell uptake.

Introduction: (99m)Tc-BnAO is one of the nonnitroimidazole hypoxia markers with the highest citation and could be potentially useful in both oncology and other clinical applications. However, it appears inferior in vitro due to lower absolute accumulation and smaller anoxic/normoxic uptake ratio. It is possible that the analogues of (99m)Tc-BnAO have higher hypoxia selectivity after the ligand of (99m)Tc-BnAO is modified.