Synthesis,radiolabeling and biological distribution of a new dioxime derivative as a potential tumor imaging agent

A novel dioxime derivative (2E,2′E,3E,3′E)-3,3′-(pyrimidine-4,5-diylbis(azanylylidene))bis(butan-2-one)dioxime was synthesized with a yield of 65%. IR, elemental analysis, mass spectroscopy and ¹H-NMR were used to characterize the structure of the synthesized compound. ^99mTc-dioxime was radio-synthesized with a high radiochemical yield of 97.8 ± 0.5% and in vitro stability of 6 h under the optimum conditions. The preclinical evaluation of ^99mTc-dioxime in solid tumor-bearing mice showed high accumulation in solid tumor cells with a high Target/Non-Target ratio of 5.14 at 30 min post-injection. This study suggests that ^99mTc-dioxime derivative is a promising candidate as a new ^99mTc-based tumor-imaging agent after further preclinical studies.     

Radiolabeling of gemifloxacin with technetium-99m and biological evaluation in artificially <Emphasis Type="Italic">Streptococcus pneumoniae</Emphasis> infected rats

In the current investigation complexation of the gemifloxacin (GIN) with technetium-99 m (^99mTc) and its biological evaluation in artificially Streptococcus pneumoniae (S. pneumoniae) infected rats was assessed as potential S. pneumoniae infection radiotracer. Radiochemically the ^99mTc-GIN complex was further analyzed in terms of stability in saline, in vitro stability in serum at 37 °C, in vitro binding with S. pneumoniae and biodistribution in artificially S. pneumoniae (living and heat killed) infected rats. The complex was found 97.25 ± 0.25% radiochemically stable in saline at 30 min after reconstitution. The stability of the ^99mTc-GIN complex was decreased to 90.50 ± 0.20% within 240 min after reconstitution. In serum the ^99mTc-GIN complex showed stable profile with the appearance of 18.85% free tracer within 16 h of incubation. The ^99mTc-GIN complex showed saturated in vitro binding with S. pneumoniae after different intervals. Almost five fold uptake was observed in living S. pneumoniae infected muscle of the rats as compared to the inflamed and normal muscle. No significant difference in the uptake of heat killed S. pneumoniae infected, inflamed and normal muscles of the rats. The high RCP yield in saline, in vitro permanence in serum, in vitro binding with living S. pneumoniae and biodistribution in artificially S. pneumoniae infected rats we recommend the ^99mTc-GIN as potential S. pneumoniae infection radiotracer.     

A perspective on <Superscript>99m</Superscript>Tc and <Superscript>125/131</Superscript>I labeled receptor targeted compounds and their in vitro/in vivo affinities

A novel quinoline derivative, 2,2′-[(5-chloro-8-hydroxyquinoline-7-yl) methylazanediyl] diacetic acid (CHQMADA) was labeled with ^99mTc using SnCl₂·2H₂O as a reducing agent to give a complex with a labeling yield 94 %. Also [^99mTc(H₂O)₃(CO)₃]⁺ was prepared by heating at 100 °C for 30 min using 2 mg CHQMADA at pH 8 to give a labeling yield >99 %. ^99mTc-(CO)₃ CHQMADA and ^99mTc-Sn(II)-CHQMADA showed tissue uptake (target to non target T/NT = 6.80 ± 0.22) and (T/NT = 5.65 ± 0.34) respectively in Escherichia coli induced infection, which is higher than the commercially available ^99mTc-ciprofloxacin (T/NT = 3.80 ± 0.80). In conclusion, both complexes were able to differentiate between septic and aseptic inflammation with superiority of [^99mTc-(CO)₃ CHQMADA].     

Radiosynthesis and Biodistribution of <Superscript>99m</Superscript>Tc-Metronidazole as an <Emphasis Type="Italic">Escherichia coli</Emphasis> Infection Imaging Radiopharmaceutical

Bacterial infection poses life-threatening challenge to humanity and stimulates to the researchers for developing better diagnostic and therapeutic agents complying with existing theranostic techniques. Nuclear medicine technique helps to visualize hard-to-diagnose deep-seated bacterial infections using radionuclide-labeled tracer agents. Metronidazole is an antiprotozoal antibiotic that serves as a preeminent anaerobic chemotherapeutic agent. The aim of this study was to develop technetium-99m-labeled metronidazole radiotracer for the detection of deep-seated bacterial infections. Radiosynthesis of ^99mTc-metronidazole was carried by reacting reduced technetium-99m and metronidazole at neutral pH for 30 min. The stannous chloride dihydrate was used as the reducing agent. At optimum radiolabeling conditions, ~ 94% radiochemical was obtained. Quality control analysis was carried out with a chromatographic paper and instant thin-layer chromatographic analysis. The biodistribution study of radiochemical was performed using Escherichia coli bacterial infection-induced rat model. The scintigraphic study was performed using E. coli bacterial infection-induced rabbit model. The results showed promising accumulation at the site of infection and its rapid clearance from the body. The tracer showed target-to-non-target ratio 5.57 ± 0.04 at 1 h post-injection. The results showed that ^99mTc-MNZ has promising potential to accumulate at E. coli bacterial infection that can be used for E. coli infection imaging.     

Synthesis and biological distribution of 99mTc–norfloxacin complex, a novel agent for detecting sites of infection

The optimization of the radiolabeling yield of ciprofloxacin analogous, norfloxacin, with technetium-99m (^99mTc) was described. Dependence of the labeling yield of ^99mTc–norfloxacin complex on the concentration of norfloxacin, SnCl₂·2H₂O content, pH of the reaction mixture and reaction time was studied. Norfloxacin was labeled with ^99mTc at pH 3 with a labeling yield of 95.4% by using 5 mg norfloxacin, 50 μg SnCl₂·2H₂O and 30 min reaction time. The formed ^99mTc–norfloxacin complex was stable for a time up to 3 h. Biological distribution of ^99mTc–norfloxacin complex was investigated in experimentally induced inflammation rats using Staphylococcus aureus (bacterial infection model) and heat killed Staphylococcus aureus and turpentine oil (sterile inflammation model). In case of bacterial infection, the T/NT value for ^99mTc–norfloxacin complex was found to be 6.9 ± 0.4 which was higher than that of the commercially available ^99mTc–ciprofloxacin under the same experimental condition.     

Solid targets for 99mTc production on medical cyclotrons

Recent disruptions in the molybdenum-technetium generator supply chain prompted a review of non-reactor based production methods for both ⁹⁹Mo and ^99mTc. Small medical cyclotrons (E _p ~ 16–24 MeV) are capable of producing Curie quantities of ^99mTc from isotopically enriched ¹⁰⁰Mo using the ¹⁰⁰Mo(p,2n)^99mTc reaction. Unlike most other metallic target materials for routine production of medical radioisotopes, molybdenum cannot be deposited by reductive electroplating from aqueous salt solutions. To overcome this issue, we developed a new process for solid molybdenum targets based on the electrophoretic deposition of fine ¹⁰⁰Mo powder onto a tantalum plate, followed by high temperature sintering. The targets obtained were mechanically robust and thermally stable when irradiated with protons at high power density.     

Interaction between green tea extract and 99mTc-pertechnetate on in vivo distribution

People drink various types of tea without knowing the side effects of biological and chemical contents and radiopharmaceutical interactions. In current study, it is aimed to evaluate the effects of green tea extract in different extraction solvents on the radiolabeling of the blood constituents with ^99mTc and on the biodistribution of radiopharmaceutical sodium pertechnetate (Na^99mTcO₄) in male Wistar Albino rats. The extraction of green tea was performed in different solvents. Biodistribution studies were performed on male rats which were treated via gavage with green tea extract in different extraction solvents or saline (0.9 % NaCl) as a control group for 7 days. The radiolabeling of blood constituents performed incubating with SnCl₂ and ^99mTc. According to experimental results, radiolabeling blood components with ^99mTc were not modified in the usage of the different extraction solvents for green tea extraction, but a significant alteration (P < 0.05) of biodistribution of Na^99mTcO₄ was observed after treatment with green tea extract in distilled water. Although there is no considerable effect on radiolabeling of blood components, there is an outstanding change on the biodistribution studies especially with green tea extract in distilled water. The identified change monitored in this study may cause to reduce the risk of misdiagnosis and/or avoid the repetition of the examinations in nuclear medicine.     

Synthesis and preliminary biological evaluation of a technetium-99m labeled thymidine analog

The synthesis and labeling of ^99mTc-N³-（N’-[2-sulfanyl-ethylamino）acetyl]-2-aminoethyl-sulfanyl-1-hexanamide}thymidine (^99mTc-NHT) were studied.In the presence of sodium glucoheptonate（GH） and ethylene diamine tetraacetic acid（EDTA）,^99mTc-NHT was obtained by using bisaminoethanethiol（N₂S₂） as a bifunctional coupling agent.The radiochemical purity of the ^99mTc-NHT was over 95%.Biodistribution of ^99mTc-NHT was performed in hepatoma HepA tumor-bearing mice.At 2 h p.i.,the ratios of tumor-to-muscle,tumor-to-bone and tumor-to-blood were 4.41±0.32,2.45±0.24 and 1.51±0.18,respectively.     

Preparation and biological distribution of 99mTc-cefazolin complex, a novel agent for detecting sites of infection

The optimization of the radiolabeling yield of cefazolin with ^99mTc was described. Dependence of the labeling yield of ^99mTc-cefazolin complex on the amounts of cefazolin and SnCl₂·2H₂O, pH and reaction time was studied. Cefazolin was labeled with ^99mTc with a labeling yield of 89.5 % by using 1 mg cefazolin, 5 μg SnCl₂·2H₂O at pH 4 and 30 min reaction time. The radiochemical purity of ^99mTc-cefazolin was evaluated with ITLC. The formed ^99mTc-cefazolin complex was stable for a time up to 3 h, after that the labeling yield decreased 64.0 % at 8 h. Biological distribution of ^99mTc-cefazolin complex was investigated in experimentally induced inflammation mice, in the left thigh, using Staphylococcus aureus (bacterial infection model) and turpentine oil (sterile inflammation model). Both thighs of the mice were dissected and counted and the ratio of bacterial infected thigh/contralateral thigh was then evaluated. In case of bacterial infection, T/NT for ^99mTc-cefazolin complex was 8.57 ± 0.4 after 0.5 h, which was higher than that of the commercially available ^99mTc-ciprofloxacin under the same experimental conditions. The ability of ^99mTc-cefazolin to differentiate between septic and aseptic inflammation indicates that ^99mTc-cefazolin could undergo further clinical trials to be used for imaging sites of infection.     

Biodistribution of ultra small superparamagnetic iron oxide nanoparticles in BALB mice

Recently ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles (NPs) have been widely used for medical applications. One of their important applications is using these particles as MRI contrast agent. While various research works have been done about MRI application of USPIOs, there is limited research about their uptakes in various organs. The aim of this study was to evaluate the biodistribution of dextran coated iron oxide NPs labelled with ^99mTc in various organs via intravenous injection in Balb/c mice. The magnetite NPs were dispersed in phosphate buffered saline and SnCl₂ which was used as a reduction reagent. Subsequently, the radioisotope ^99mTc was mixed directly into the reaction solution. The labeling efficiency of USPIOs labeled with ^99mTc, was above 99 %. Sixty mice were sacrificed at 12 different time points (From 1 min to 48 h post injections; five mice at each time). The percentage of injected dose per gram of each organ was measured by direct counting for 19 harvested organs of the mice. The biodistribution of ^99mTc-USPIO in Balb/c mice showed dramatic uptake in reticuloendothelial system. Accordingly, about 75 percent of injected dose was found in spleen and liver at 15 min post injection. More than 24 % of the NPs remain in liver after 48 h post-injection and their clearance is so fast in other organs. The results suggest that USPIOs as characterized in our study can be potentially used as contrast agent in MR Imaging, distributing reticuloendothelial system specially spleen and liver.     

Expression and Characterization of Hyperthermotolerant Xylanases,SyXyn11P and SyXyn11E,in Pichia pastoris and Escherichia coli

Both Syxyn11P and Syxyn11E, two codon-optimized genes encoding glycoside hydrolase (GH) family 11 hyperthermotolerant xylanases (designated SyXyn11P and SyXyn11E), were synthesized and inserted into pPIC9K^M and pET-28a(+) vectors, respectively. The resulting recombinant expression vectors, pPIC9K^M-Syxyn11P and pET-28a(+)-Syxyn11E, were transformed into Pichia pastoris GS115 and Escherichia coli BL21, respectively. The maximum activities of two recombinant xylanases (reSyXyn11P and reSyXyn11E) expressed in P. pastoris and E. coli reached 30.9 and 17.8 U/ml, respectively. The purified reSyXyn11P and reSyXyn11E displayed the same pH optimum at 6.5 and pH stability at a broad range of 4.5–9.0. The temperature optimum and stability of reSyXyn11P were 85 and 80 °C, higher than those of reSyXyn11E, respectively. Their activities were not significantly affected by metal ions tested and EDTA, but strongly inhibited by Mn²⁺ and Ag⁺. The K _m and V _max of reSyXyn11P toward birchwood xylan were 4.3 mg/ml and 694.6 U/mg, whose K _m was close to that (4.8 mg/ml), but whose V _max was much higher than that (205.6 U/mg) of reSyXyn11E. High-performance liquid chromatography analysis indicated that xylobiose and xylotriose as the major products were excised from insoluble corncob xylan by reSyXyn11P.     

Experimental cross section evaluation for innovative 99Mo production via the (α,n) reaction on 96Zr target

The high-specific activity ⁹⁹Mo accelerator-based production, via the (α,n) reaction on ⁹⁶Zr-enriched target, has been investigated in the present work. The excitation function measurement has been performed in the energy range 8–34 MeV at the ARRONAX facility, using the well-known stacked foils technique on natural zirconium as target. A general good agreement in the cross section trend has been observed, once compared to former measurements. A different (i.e. higher) peak value and a shift of about 2 MeV towards larger energies have however been found. Assuming a fully enriched ⁹⁶Zr target irradiated by an α-beam at suitable energy (E = 25 MeV), the ⁹⁹Mo production yield has thus been estimated. At last the alternative production routes, based on the ⁹⁶Zr(α,n)⁹⁹Mo and ¹⁰⁰Mo(p,x)⁹⁹Mo/^99mTc reactions, are compared.     

Synthesis of techentium-99m labeled clinafloxacin (99mTc�CCNN) complex and biological evaluation as a potential Staphylococcus aureus infection imaging agent

In the present study synthesis of the ^99mTc?CCNN complex and its efficacy as a prospective Staphylococcus aureus (S. aureus) infection imaging agent was assessed. The ^99mTc?CCNN complex was characterized in terms of stability in saline, serum, in vitro binding with S. aureus and in vivo percent absorption in male Wister rats (MWR) infected with live and heat killed S. aureus. Radiochemically the ^99mTc?CCNN complex showed stable behavior in saline and serum at different intervals. At 30 min after reconstitution the complex showed maximum radiochemical purity (RCP) yield of 97.55 ± 0.22%. The RCP yield decreased to 90.50 ± 0.18% within 240 min. In serum, 18.15% unwanted side product was appeared within 16 h of the incubation. In vitro saturated binding with S. aureus was observed at different intervals with a 62.00% maximum at 90 min. Normal percent in vivo uptake was observed in MWR artificially infected with live S. aureus with a five times higher in the infected muscle as compared to the inflamed and normal muscles. No difference in the percent uptake of the complex in MWR infected with heat killed S. aureus in the infected, inflamed and normal muscles were observed. Based on the promising in vitro and in vivo radiochemical and biological characteristics, we recommend the ^99mTc?CCNN complex for in vivo localization of the S. aureus infectious foci.     

Effect of functionalized multiwall carbon nanotubes on the curing kinetics and reaction mechanism of bismaleimide–triazine

Functionalized multiwall carbon nanotubes (f-MWCNTs) with varying functionalization degrees were prepared by chemical methods. The effect of f-MWCNTs on the cure kinetics of bismaleimide–triazine (BT) resin was studied through nonisothermal differential scanning calorimetry (DSC) methods. The reaction activation energy (E _α ) was determined by Flynn–Wall–Ozawa method. The results show that f-MWCNTs have more acceleration ability than pristine MWCNTs, due to more groups on the surface of f-MWCNTs than that of pristine MWCNTs. The activation energy was decreased from a value of 91.3 kJ mol^?1 for the neat BT resin to 74.2 kJ mol^?1 at the small mass loading (1.0 %) of f7-MWCNTs. The effect of f-MWCNTs on the reaction mechanism has been investigated. It shows that the f-MWCNTs accelerate the cure reaction of BT resin by providing the Lewis acids (H⁺) to make the “Diels–Alder” reaction and “ENE” reaction of BT resins more efficient. These findings offer useful insights into the cure technology of thermosetting resin filled with f-MWCNTs, without negative effect on the cure reaction.     

Biodistribution of the bone imaging agents99mTc-DHPE and99mTc-MDP in rats

The self life of the freeze-dried formulation kits utilized for the preparation of the new bone imaging radiopharmaceutical^99mTc-1,2-dihydroxy-1,2-bis/dihydroxyphosphinyl/ethane /^99mTc-DHPE/ has been investigated as well as the toxicity of the DHPE. In a biodistribution investigation of^99mTc-DHPE in rats, in comparison to^99mTc-methylenediphosphanate /^99mTc-MDP/,^99mTc-DHPE exhibited a certain extent higher skeleton uptake, a higher blood clearance rate, a very low concentration in other organs, a satisfactory biological stability and excretion primarily through the kidneys. These properties demonstrate that^99mTc-DHPE is a new promising skeleton imaging radio-pharmaceutical.     

Radiocharacterization of the 99mTc�Crufloxacin complex and biological evaluation in Staphylococcus aureus infected rat model

^99mTc?Crufloxacin (^99mTc?CRUN) complex was prepared by reaction of different amounts of reduced sodium pertechnetate with different amount of Rufloxacin (RUN) antibiotic for the in vivo scintigraphic localization of the Staphylococcus aureus (S. aureus) infectious foci in Male Wister Rats (MWR) model. The ^99mTc?CRUN complex was radiochemically and biologically characterized in terms of radiochemical stability in saline, serum, in vitro binding with S. aureus and biodistribution in artificially infected with S. aureus MWR. The ^99mTc?CRUN complex showed stability more than 90% up to 240 min in normal saline with a maximum stability value of 98.10 ± 0.18% at 30 min after reconstitution. At 37 °C the complex showed in vitro permanence in serum up to 16 h with 13.90% side products during incubation. The ^99mTc?CRUN complex showed saturated in vitro binding with S. aureus at different intervals with a maximum uptake value of 71.50%. Infected to normal muscle, infected to inflamed and inflamed to normal muscles ratios were approximately 6.04, 4.31 and 1.40. Based on the stability of the complex in saline, serum, in vitro binding with S. aureus and biodistribution results, the ^99mTc?CRUN complex is recommended for in vivo scintigraphic localization of the S. aureus in vivo infectious foci in human.     

Practicality of Tetragonal Nano-Zirconia as a Prospective Sorbent in the Preparation of 99Mo/99mTc Generator for Biomedical Applications

The feasibility of using tetragonal nano-zirconia (t-ZrO₂) as an effective sorbent for developing a ⁹⁹Mo/^99mTc chromatographic generator was demonstrated. The structural characteristics of the sorbent matrix were investigated by different analytical techniques such as XRD, BET surface area analysis, FT-IR, TEM etc. The material synthesized was nanocrystalline, in tetragonal phase with an average particle size of ~7 nm and a large surface area of 340 m² g^?1. The equilibrium sorption capacity of t-ZrO₂ is >250 mg Mo g^?1. The present study indicates that ⁹⁹Mo is both strongly and selectively retained by t-ZrO₂ at acidic pH and ^99mTc could be readily eluted from it, using 0.9% NaCl solution. A 9.25 GBq (250 mCi) t-ZrO₂ based chromatographic ⁹⁹Mo/^99mTc generator was developed and its performance was repeatedly evaluated for 10 days. ^99mTc could be eluted with >85% yield having acceptable radionuclidic, radiochemical and chemical purity for clinical applications. The compatibility of the product in the preparation of ^99mTc labeled formulations such as ^99mTc-EC and ^99mTc-DMSA was evaluated and found to be satisfactory.     

Evaluation of labelling conditions,quality control and biodistribution study of 99mTc-5-aminolevulinic acid (5-ALA): a potential liver imaging agent

Labelling of 5-aminolevulinic acid (5-ALA) with ^99mTc was achieved by using SnCl₂·2H₂O as reducing agent. Radiochemical purity and labelling efficiency was determined by instant thin layer chromatography/paper chromatography. Efficiency of labelling was dependent on many parameters such as amount of ligand, reducing agent, pH, and time of incubation. ^99mTc labelled 5-ALA remained stable for 24 h in human serum. Tissue biodistribution of ^99mTc-5-ALA was evaluated in Sprague–Dawley rats. Biodistribution study (% ID/g) in rats revealed that ^99mTc-5-ALA was accumulated significantly in liver, spleen, stomach and intestine after half hour, 4 and 24 h. Significant activity was noted in bladder and urine at 4 h. High liver uptake of ^99mTc-5-ALA makes it a promising liver imaging agent.     

Synthesis and evaluation of bipyrazolic derivatives as inhibitors of corrosion of C38 steel in molar hydrochloric acid

Methyl 2-(bis((3,5-dimethyl-1H-pyrazol-1-yl)methyl)amino) acetate, BT36, and methyl 2-(bis((3,5-dimethyl-1H-pyrazol-1-yl)methyl)amino)-3-(1H-indol-3-yl)propanoate, BT 43, have been synthesized. Investigation by weight-loss measurement and use of electrochemical techniques revealed the compounds are very effective inhibitors of corrosion of C38 steel in 1 M HCl solutions—percentage protection exceeded 95 % for BT43 at concentrations as low as 10^?2 M. An impedance study in the absence and presence of these compounds revealed the mechanism of protection was cathodic inhibition by polarization and charge-transfer. The Langmuir adsorption isotherm was obeyed. Quantum chemical data calculated by use of DFT at the B3LYP/6-31G* level of theory revealed a good correlation between inhibition efficiency and the molecular structure of BT36 and BT43. The highest occupied molecular orbital, the lowest unoccupied molecular orbital, the separation energy (ΔE), and the dipole moment (μ) from the inhibitor to the metal surface explain the experimental data well.     

Gelation of cassia gum by freezing and thawing

Aqueous solution of cassia gum (CG), which is categorized as a galactomannan polysaccharide having mannose/galactose ratio = 5/1, forms hydrogels by freezing and thawing. When frozen CG aqueous solution was thawed, transparent sol was separated from a turbid gel, i.e. syneresis occurred. Gel concentration ({(Mass of dry gel) / (Mass of gel)} × 100) increased with increasing CG concentration. Viscoelastic properties of CG hydrogels formed by freezing and thawing were investigated by thermomechanical analysis (TMA) in water using an oscillation mode at 0.05 Hz. Dynamic modulus (E′) increased from 3 kPa to ca. 5 kPa with increasing freezing rate. In contrast, E′ maintained a constant value regardless of repeating number of freezing and thawing. From TMA results, it is concluded that the density of cross-linking network structure depends on the size of ice formed by freezing. At the same time, the low E′ value of CG gels is ascribed to the fact that association of galactosyl side group is disturbed by the stiff chain attributed to the unsubstituted region of CG.