Preparation and bioevaluation of a novel 99mTc-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). The three compounds were radiolabeled with 99mTc to give three complexes([99mTc]Tc-Br2P2, [99mTc]Tc-Me2P2 and [99mTc]Tc-2Me2P2) with good in vitro stability. [99mTc]Tc-Me2P2 with a more suitable reduction potential had the highest hypoxic cellular uptake, compared with [99mTc]Tc-2P2 that have been previously reported, [99mTc]Tc-Br2P2 and [99mTc]Tc-2Me2P2. Biodistribution results in S180 tumor-bearing mice demonstrated that [99mTc]Tc-Me2P2 had the highest tumor-to-muscle (T/M) ratio (12.37 ± 1.16) at 2 h in the four complexes. Autoradiography and immunohistochemical staining results revealed that [99mTc]Tc-Me2P2 specifically targeted tumor hypoxic regions. The SPECT/CT imaging results showed that [99mTc]Tc-Me2P2 could target the tumor site. [99mTc]Tc-Me2P2 may become a potential hypoxia imaging agent.

Improving tumor/muscle and tumor/blood ratios of 99mTc-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 99mTc. The radiochemical purities of three 99mTc-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 (99mTc-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 (99mTc-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 (99mTc-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 2.92 ± 0.61, 2.63 ± 0.64 and 2.29 ± 0.67 in S180 cellular uptake assay (4 h). All of these complexes presented good hypoxia selectivity. The results of biodistribution studies in S180 tumor-bearing mice revealed that the tumor/muscle (T/M) ratios (7.20 ± 2.37, 7.19 ± 1.75, 5.56 ± 1.10) and tumor/blood (T/B) ratios (1.66 ± 0.34, 1.73 ± 0.25, 2.13 ± 0.19) at 4 h of three complexes were significantly higher than those of 99mTc-2P2 (3.24 ± 0.65, 0.81 ± 0.34) without the ethylene glycol chains. Among them, 99mTc-2P2O4 had the best T/B ratio. The new complexes have higher tumor/blood and tumor/muscle ratios by adding suitable length of ethylene glycol chain. It is helpful for the design and optimization of hypoxic imaging agents.

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 99mTc 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. The results of S180 cell experiment and biodistribution indicated that these molecules have different hypoxic selectivity. When contains one 2-nitroimidazole, as the carbon chain lengthens, which means the molecular volume becomes larger, hypoxia cellular uptake and selectivity decrease in S180 cell uptake experiment. In biodistribution study in mice bearing S180 tumor, Tc-2 (1-cyclopentadienyl-5-(2-nitro-1H-imidazol-1-yl)-pentan-1-one tricarbonyl 99mTc complex), which has intermediate carbon chain, is better due to the more complex factors. Its tumor/blood (T/B) ratio is 3.56 ± 0.25, tumor/muscle(T/M) ratio is 1.73 ± 0.29 and tumor uptake is 2.23 ± 0.24%ID/g at 2 h. Comparing to other tricarbonyl technetium complexes containing one 2-nitroimidazole, the complexes in this work have an advantage in tumor/blood ratio and tumor uptake. This suggests that the small-volume cyclopentadienyl may have an advantage when used as a ligand. When contains two 2-nitroimidazole groups, the complex, 1-cyclopentadienyl-5-di(2-(2-nitro-1H-imidazol-1-yl)ethyl)amino-pentan-1-one tricarbonyl 99mTc complex (Tc-4), has the better results in the cell experiment than those which contain one 2-nitroimidazole group. Thus the hypoxia imaging agent contains two 2-nitroimidazole groups is more advantageous, but further modifications of Tc-4 are needed to improve its clearance rate in the blood, because the increased lipophilicity leads to a decrease in the T/B ratio of Tc-4. In conclusion, small volume hypoxia imaging agents with two 2-nitroimidazole groups may be the trend of development.

Quaternary phosphonium modified cellulose microsphere adsorbent for 99Tc decontamination with ultra-high selectivity.

Decontamination of radioactive TcO4- 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 TcO4- 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 TcO4- adsorbents with an ultra-high selectivity, designated CMS-g-VBPPh3NO3. The prepared materials show adsorption capacities of 251 mg g-1 (for the surrogate Re). The selective factor against NO3- in 0.5 mol kg-1 HNO3 is as high as 168, showing excellent anion-exchange selectivity towards TcO4-. Moreover, CMS-g-VBPPh3NO3 was packed in column for treating simulated acidic waste solutions containing Cs, Sr, Eu, Zr, Ru, U and Re, and it showed excellent Re separation performance. Tracer amount of 99mTc experiments showed that comparing to ReO4-, CMS-g-VBPPh3NO3 has a better adsorption selectivity for TcO4-.

Direct dissolution of UO2 in carboxyl-functionalized ionic liquids in the presence or absence of Fe-containing ionic liquids.

Dissolution of UO2 is a prerequisite for the reprocessing of spent nuclear fuel. This study showed that UO2 could be directly dissolved in a single carboxyl-functionalized ionic liquid (IL), [HOOCMmim][Tf2N] 1-carboxymethyl-3-methylimidazolium bistriflimide, or [HOOCEtmim][Tf2N] 1-carboxyethyl-3-methylimidazolium bistriflimide. The addition of an extra Fe-containing IL, [Emim][FeCl4] (Emim, 1-ethyl-3-methylimidazolium) or [Bmim][FeCl4] (Bmim, 1-butyl-3-methylimidazolium) could significantly improve the dissolution kinetics. Results demonstrated that the dissolution process in the early stage could be described by using the pseudo first-order rate law. The apparent activation energy for UO2 dissolution in the mixture of the Fe-containing IL and carboxyl-functionalized IL was calculated to be ∼67 kJ mol-1, implying that the reaction was mainly controlled by a chemical process. Nevertheless, the influence of the diffusion process is non-negligible since the IL has a relatively high viscosity that can retard the diffusion of the formed uranyl species from the UO2 surface. Spectroscopic studies and density functional theory calculations indicated that the uranyl ion coordinated with carboxylate groups is the predominant product for UO2 dissolution in the single carboxyl-functionalized IL, while uranyl chloride complexes would also form in the mixed ILs. The dissolved uranyl species can be successfully recovered from the ILs by extraction. The success of UO2 dissolution in the carboxyl-functionalized IL with or without the Fe-containing IL indicates that the Fe-containing IL and oxygen can serve as an effective catalyst and oxidant for the dissolution of UO2, respectively.

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 [131I]iodide ions and evaluated by hypoxic cellular uptake and biodistribution experiments. The results suggested that radiotracers with suitable partition coefficients (log P: -0.2-1.2) were more likely to have higher hypoxic cellular uptake. Among these eight molecules, [131I]15 ([131I]-(5-iodo-1-(2-(2-(2-nitro-1H-imidazol-1-yl)ethoxy)ethyl)-4-((2-nitro-1H-imidazol-1-yl)methyl)-1H-1,2,3-triazole)) had a suitable log P (0.05 ± 0.03) and contained two 2-nitroimidazole groups. The hypoxic/aerobic cellular uptake ratio of [131I]15 was 4.4 ± 0.5, and the tumor/blood (T/B) and tumor/muscle (T/M) ratios were 2.03 ± 0.45 and 6.82 ± 1.70, respectively. These results suggested that [131I]15 was a potential hypoxia imaging agent.

Ionic liquids with polychloride anions as effective oxidants for the dissolution of UO2.

Herein, polychloride ([Cl3]- or/and [Cl5]-) ionic liquids (ILs) were prepared from their imidazolium chloride precursors by the addition of chlorine gas. The highest storage ability of Cl2 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][Tf2N] (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 1H NMR spectroscopy. It has been found that the synthesized polychloride ILs not only can successfully dissolve UO2, but can also decrease the consumption of Cl2 and increase the chlorine efficiency. Spectroscopy studies indicate that [UO2Cl4]2- is the principal product in the IL reaction solution. The dissolved uranyl species can be easily recovered from the ILs by crystallization in the form of [Bmim]2[UO2Cl4]. Moreover, even if 57.1 wt% of the lanthanide element, when compared with the total amount of dissolved uranium and lanthanide elements, was dissolved in the IL mixture, only uranium-containing crystals could be isolated from the system.

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. 18F-fluorodeoxyglucose (18F-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. For a long time different researchers and groups of pharmacists have tried to label glucose with a cheaper and long-acting radionuclide like 99mTc. However, they failed to achieve this goal owing to the chemical complexity of 99mTc and the lack of maintaining the physiological activity of diagnostic compounds. A pre-targeting strategy based on strain-promoted [3 + 2] azide-alkyne cycloaddition (SPAAC) reaction was applied to solve this problem. Functional click synthons were synthesized: 2-azido-2-deoxy-d-glucose (GlucN3) as a glucose analogue, and N- (2- (2- (2- (bis (pyridin-2-ylmethyl) amino) ethoxy) ethoxy) ethyl-2- (6H-11,12-didehydrodibenzo [a,e] cycloocten-5-ylideneaminooxy) acetamide (C7) as a 99mTc(CO)3 labeling and azido-binding group. The results of biodistribution experiments in mice bearing S180 tumor show the relatively high tumor/blood ratio (up to 2.95) and tumor/muscle ratio (up to 6.37), and both of them decreases significantly in the glucose blocking experiment. It indicates that GlucN3 behaves similarly to glucose and that in vivo SPAAC reactions can occur effectively. It is supposed that this pre-targeting strategy can indeed enhance target specificity and may be used for glucose metabolism imaging in tumor diagnosis.

Synthesis and Bioevaluation of Novel [18F]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 [18F]FDG in high radiochemical yield and excellent radiochemical purity. Cell experiments, biodistribution, and positron emission tomography (PET) imaging studies were also conducted in mice-bearing S180 or OS732 tumors. [18F]FDG-2NNC2ON [(2 R,3 S,4 R, E)-2-18F-fluoro-3,4,5,6-tetrahydroxyhexanal O-3-(2-(2-nitro-1 H-imidazole-1-yl)ethylamino)-2-oxopropyl oxime] and [18F]FDG-2NNC5ON [(2 R,3 S,4 R, E)-2-18F-fluoro-3,4,5,6-tetrahydroxyhexanal-O-3-(5-(2-nitro-1 H-imidazole-1-yl)pentylamino)-2-oxopropyl oxime] can be cleared from the blood quickly and specifically target hypoxic tumor cells. The uptake of the probes by hypoxic cells gradually increases with time. After 4 h, the uptake value of [18F]FDG-2NNC2ON in hypoxic cells is 3.2 times higher than that in normoxia cells. In contrast, there is no difference in the uptake of [18F]FDG between hypoxic cells and normoxia cells. Biodistribution resulting from two tumor models indicate that the uptake values of the two radiotracers in the tumor are higher at 1 h than those at 2 and 4 h. At 1 and 2 h, the tumors are clearly observed on the PET images and the imaging features of [18F]FDG-2NNC5ON and [18F]FDG-2NNC2ON are distinct from those of [18F]FDG. Compared with [18F]FDG-2NNC5ON, [18F]FDG-2NNC2ON has a higher proportion of renal excretion, lower digestive tract uptake, and better imaging contrast because of its higher hydrophilicity. At 2 h, [18F]FDG-2NNC2ON shows a good tumor-to-blood (T/B) ratio, tumor-to-muscle ratio based on biodistribution (Bio-T/M ratio), and tumor-to-muscle ratio based on regions of interest on the PET images [region of interest (ROI)-T/M ratio] in the two tumor models (T/B, Bio-T/M, and ROI-T/M ratios are 3.2, 2.6, and 3.9 in the S180 tumor model and are 3.4, 4.2, and 4.6 in the OS732 tumor model, respectively). The imaging features visualized with autoradiography mostly coincided with the positive areas of HIF1α staining by immunofluorescence. Meanwhile, the biodistribution study and PET imaging revealed that the uptake of the radiotracers in the tumor cannot be competed by 5% glucose, confirming that [18F]FDG-2NNC2ON targets the hypoxic regions of the tumors instead of targeting tumors through the glucose metabolism pathway. These results suggest that the new 2-nitroimidazole derivative conjugated with [18F]FDG, [18F]FDG-2NNC2ON, has potential as an imaging agent for hypoxia.

A two-step strategy to radiolabel choline phospholipids with 99mTc 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 99mTc 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. Functional click synthons were synthesized as pretargeting components: azidoethyl-choline (AECho) serves as tumor marker and azadibenzocyclooctyne (ADIBO) conjugated to bis(2-pieolyl) amine (BPA) ligand (ADIBO-BPA) as 99mTc(CO)3-labeling and azido-binding group. Both in vitro cell experiment and in vivo biodistribution experiment indicate that it is versatile to radiolabel Cho in cellular membranes via this two-step pretargeting strategy. We believe that this pretargeting strategy can indeed enhance the target-specificity and also reduce background signals to optimize imaging quality.

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. These unique properties suggest that the as-prepared FCNVs could be applied as an ideal theranostic agent for simultaneous imaging and photodynamic therapy of tumor. This finding may provide a good solution to highly efficient phototheranostic applications based on fullerene derivatives fabricated nanostructures.

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. These results suggest that (64)Cu-BMS2P2 is a promising candidate for PET hypoxia imaging and worthy of further investigations in dynamic hypoxia imaging.

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. Some comparisons were made with the other complexes of our previous work, and some interesting conclusions were obtained. (99m) Tc-1 and (99m) Tc-2 displayed significant hypoxic/normoxic differentials in both S180 and H22 cell lines. These complexes held moderate tumor-to-blood and tumor-to-muscle ratios, indicating they might serve as novel hypoxia markers. Some comparisons showed the in vitro evaluation may be connected with the number and the type of the redox centers, and the biodistribution experiments may have relation with the hydrophilicity and the type of redox centers.

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. 2NIM-triazole-MAMA was obtained from in vitro click reaction with a reaction rate constant of 0.98M(-1)s(-1). AM and 2NIM-triazole-MAMA were radiolabeled with Tc-99m. The hypoxia-pretargeting biodistribution was studied in Kunming mice bearing S180 tumor; (99m)Tc-AM and (99m)Tc-triazole-2NIM were used as blank control and conventional control. Compared to the control groups, the pretargeting experiment exhibits the best radio-uptake and retention in tumor, with higher tumor-to-muscle and tumor-to-blood ratios (up to 8.55 and 1.44 at 8h post-(99m)Tc-complex-injection, respectively). To some extent, the pretargeting strategy protects the bioactivity of nitroimidazole and therefore provides an innovative approach for the development of tumor hypoxia-SPECT imaging agents.

Radioactive lutetium metallofullerene 177LuxLu(3-x)N@C80-PCBPEG derivative: a potential tumor-targeted theranostic agent.

A radioactive metallofullerene 177LuxLu(3-x)N@C80 was firstly synthesized by means of neutron irradiation on Lu3N@C80. 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 177LuxLu(3-x)N@C80-PCBPEG could be promising for tumor diagnosis and therapy.

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. The key features of the biological evaluation include the following: (1) the autoradiogram of (99m)Tc-N4IPA complex in tissue samples of hypoxia overlaps with the area stained by hypoxyprobe-1; (2) SPECT imaging of U87-bearing mice clearly identifies tumors 4 h post injection of (99m)Tc-N4IPA, reaching ID% of 8.48 ± 4.51; (3) the main pathways of excretion of (99m)Tc-N4IPA are through kidneys and livers in both A549 or U87-bearing tumor mice.

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. The dissolved uranyl species can be successfully separated from the Fe-containing ILs via a combination of centrifugation and solvent extraction, and also, the Fe-containing ILs can be recovered easily. In conclusion, imidazolium-based Fe-containing ionic liquids in the presence of imidazolium chlorides could be used as effective and recoverable oxidants for the dissolution of UO2.

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+). The UV-vis spectra of [UO(2)(TEMBP)(2)](2+) in acetonitrile and in the two ILs are similar. The vibronic fine structures in UV-vis spectrum of [UO(2)(TEMBP)(2)](2+) show characters of tetragonal coordination in the uranyl equatorial plane. The symmetry of proposed structure of [UO(2)(TEMBP)(2)](2+) is D(2h), and its UV-vis spectrum is tentatively interpreted based on the structural similarity to the well studied [UO(2)Cl(4)](2-) complex. The luminescence emission spectrum of [UO(2)(TEMBP)(2)](2+) shows typical vibronic bands, having a mirror relationship with the 455-500 nm region of the corresponding absorption spectrum. The stoichiometry of [UO(2)(TEMBP)(2)](2+) is confirmed by electrospray ionization-ion trap mass spectrometry (ESI-ITMS) studies with acetonitrile as solvent. The "naked" dication (m/z 423) is characterized by the remarkable eight peaks with interval of 14 m/z units in its tandem mass spectra, representing the fragmentation of ligands by losing C(2)H(4) units from their ethoxy groups. However, the dication tends to exist as a weak adduct with either an additional ligand or an anion in the ESI mass spectrum. The adducts {[UO(2)(TEMBP)(2)](2+) + TEMBP} (m/z 567) and {[UO(2)(TEMBP)(2)](2+) + [ClO(4)](-)} (m/z 945) are favorable in pure acetonitrile, while only one adduct {[UO(2)(TEMBP)(2)](2+) + [NTf(2)](-)} (m/z 1126) is predominant in [BMIm][NTf(2)] (diluted with acetonitrile). The results of ESI-ITMS study are consistent with those of optical spectroscopic studies.

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)). Reduction potentials of nitro groups of the rhenium complexes are within the range for bioreductive compounds. As expected, biodistribution studies demonstrate that the 2-nitroimidazole complex shows better tumor-to-tissue ratios than 4-nitroimidazole analog for mononitroimidazole complexes, but not for MAMA-bisnitroimidazoles due to higher lipophilicity. Both the bisnitroimidazole compounds show rapider excretion, lower background activity in liver and higher tumor-to-tissue ratios than the mononitroimidazoles. Better biodistribution characteristic makes both the MAMA-bisnitroimidazole complexes, especially (99m)Tc-15, be potential tumor hypoxia marker.

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 33.7 ± 0.2% and 35.0 ± 0.7% at 4 h, whereas the normoxic uptakes of the two complexes were 6.0 ± 1.6% and 4.6 ± 0.9%, respectively. Both (99m)Tc-1 and (99m)Tc-2 displayed significant anoxic/normoxic differentials. The cellular uptakes were highly dependent on oxygen and temperature. Biodistribution studies revealed that both (99m)Tc-1 and (99m)Tc-2 showed a selective localization in tumor and slow clearance from it. At 4 h, the tumor-to-muscle ratios (T/M) were 3.79 for (99m)Tc-1 and 4.58 for (99m)Tc-2. These results suggested that (99m)Tc-labeled PnAO complexes (99m)Tc-1 and (99m)Tc-2 might serve as novel hypoxia markers. By introducing a second nitrotriazole redox center, the hypoxic accumulation of the marker was slightly enhanced.