Nucleophilic aromatic substitution by [<Superscript>18</Superscript>F]fluoride at substituted 2-nitropyridines

For the radiofluorination of benzenes and benzene derivatives, the electrophilic reaction with [¹⁸F]F₂ is a very common route. Yet, aromatic nucleophilic substitution (S_NAr) by n.c.a [¹⁸F]fluoride, which can be produced efficiently in high amounts, has been considered to be very desirable. However, to facilitate ¹⁸F-labelling via S_NAr at an electron rich aromatic system, an appropriate leaving group must be present together with an auxiliary group in ortho or para position to the leaving group. An interesting alternative for the auxiliary group is the heteroatom of a heteroaromatic system, for which pyridine is a leading example. Dolci et al. (J Label Compd Radiopharm 42:975–985, 1999) have evaluated the scope of the nucleophilic aromatic fluorination of 2-substituted pyridine rings using the activated K [¹⁸F]F-K₂₂₂ complex. As methyl and methoxy groups are known to enhance the electron density of an aromatic system by the +I and the +M effect, respectively, S_NAr is unlikely to occur. Until now, the effect of these substituents has not been studied towards the ¹⁸F-radiofluorination of substituted 2-nitropyridines by use of [¹⁸F]fluoride. Therefore, we have investigated the effect of methoxy and methyl groups in 2-nitropyridines. The results showed that 3-methoxy-2-nitropyridine and 3-methyl-2-nitropyridine can efficiently be substituted by [¹⁸F]fluoride with high RCY’s (70–89%) in short reaction times (1–30 min) at a reaction temperature of 140 °C. Moreover, 3-methoxy-6-methyl-2-[¹⁸F]fluoropyridine was obtained from the corresponding nitro-precursor in a high yield of 81 ± 1% after 30 min at 140 °C. In case of 2-nitropyridines data indicates the effect of methyl and methoxy groups on S_NAr to be of minor importance.     

Determination of <Superscript>90</Superscript>Sr, <Superscript>129</Superscript>I and gross beta radioactivity concentration in some teas

In this study, ⁹⁰Sr (540 keVβ ⁻), ¹²⁹I (150 keVβ ⁻) and the gross beta radioactivity concentrations were determined for the samples of tea as the most leading consumed hot drink in the markets (processed and packaged for sale) in our country. Furthermore, the obtained data were statistically analyzed. For determination of ¹²⁹I (150 keVβ⁻), ⁹⁰Sr (540 keVβ⁻) and gross radioactivity concentrations in tea samples, a sensor system consisting of scintillation detector with BP4 probe sensitive to beta radiation and a radiation meter (ST7) configurable for windows at desired power was used.     

Radiofluorination of 2-fluoropyridines by isotopic exchange with [<Superscript>18</Superscript>F]fluoride

In homoaromatic systems, isotopic exchange (¹⁸F/¹⁹F) was previously (J Label Compd Radiopharm 18(12):1721–1730 [2], J Chem Soc Perkin Trans 1(3):295–298 [3]) proven to be advantageous, yet in general specific activity is thought to be low. For heteroaromatic systems, in particular, very few examples are published regarding the ¹⁸F-labelling of 2-substituted pyridines (J Label Compd Radiopharm 42:975–985 [9]). Therefore, in 2-fluoropyridines, we decided to study the ¹⁸F labelling by isotopic exchange (¹⁸F/¹⁹F). The radiochemical yield for 2-fluoropyridine was 90 ± 2%. Even if 2-fluoropyridine was substituted by an electron-donating group such as a methyl or a methoxy group, radiochemical yields were 80 ± 1 and 78 ± 1%, respectively. Although in benzenes, these substituents are known to decrease nucleophilic substitutions by ¹⁸F-Fluoride significantly. Moreover, by choosing appropriate concentrations of 2-fluoropyridines, reasonably high specific activities up to 10 GBq/μmol were obtained.     

The concentration of <Superscript>238</Superscript>U and the levels of gross radioactivity in surface waters of the Van Lake (Turkey)

Gross α and gross β activities and ²³⁸U concentrations were determined in 18 surface water samples collected from Van Lake. The instrumentations used to count the gross α and gross β activities and to determine the ²³⁸U concentrations were α/β counter of the multi-detector low background system (PIC-MPC-9604) and Inductively Coupled Plasma-Mass Spectrometry (Thermo Scientific Element 2), respectively. Concentrations ranging from 0.001 to 0.021 Bq L⁻¹ and from 0.111 to 2.794 Bq L⁻¹ were observed for the gross α and β activities in surface waters, respectively. For all samples the gross β activities were higher than the corresponding gross α activities. The results indicated that the gross α radioactive contamination in water samples was lower than recommended values for the guideline of drinking waters and most of the gross β activities in water samples were higher than those in the same procedure. The ²³⁸U concentrations ranged from 74.49 to 113.2 μg L⁻¹ in surface waters. The obtained results have showed that ²³⁸U concentrations are higher than guideline values for uranium.     

Fully automated radiosynthesis of [<Superscript>18</Superscript>F]Fluoromisonidazole with single neutral alumina column purification: optimization of reaction parameters

1-H-1-(3-[¹⁸F]fluoro-2-hydroxypropyl)-2-nitroimidazole ([¹⁸F]FMISO), is the most used hypoxia-imaging agent in oncology and we have recently reported a fully automated procedure for its synthesis using the Nuclear Interface FDG module and a single neutral alumina column for purification. Using 1-(2′-nitro-1′-imidazolyl)-2-O-tetra-hydropyranyl-3-O-toluenesulfonylpropanediol (NITTP) as the precursor, we have investigated the yield of [¹⁸F]FMISO using different reaction times, temperatures, and the amount of precursor. The overall yield was 48.4 ± 1.2% (n = 3), (without decay correction) obtained using 10 mg NITTP with the radio-fluorination carried out at 145 °C for 3 min followed by acid hydrolysis for 3 min at 125 °C in a total synthesis time of 32 ± 1 min. Increasing the precursor amount to 25 mg did not improve the overall yield under identical reaction conditions, with the decay uncorrected yield being 46.8 ± 1.6% (n = 3), but rather made the production less economical. It was also observed that the yield increased linearly with the amount of NITTP used, from 2.5 to 10 mg and plateaued from 10 to 25 mg. Radio-fluorination efficiency at four different conditions was also compared. It was also observed by radio thin layer chromatography (radio-TLC) that the duration of radio-fluorination of NITTP, not the radio-fluorination temperature favoured the formation of labeled thermally degraded product, but the single neutral alumina column purification was sufficient enough to obtain [¹⁸F]FMISO devoid of any radiochemical as well as cold impurities.     

Determination of activity ratios of <Superscript>238,239+240,241</Superscript>Pu, <Superscript>241</Superscript>Am, <Superscript>134,137</Superscript>Cs,and <Superscript>90</Superscript>Sr in Bulgarian soils

The origins of different artificial radionuclides found in soils from Northern and Southern Bulgaria was determined by measurements of their actual concentrations and respective ratios. On the basis of the measured mobility and concentrations of the investigated radionuclides in soils, it was estimated that after the Chernobyl accident the mean depositions of fresh ¹³⁷Cs were 3.0 ± 2.5 kBq/m² for Northern Bulgaria and 15 ± 7 kBq/m² for Southern Bulgaria. As a result of global fallout following atmospheric nuclear weapon tests in the 1950s, mean depositions (corrected to 1965) were calculated for Northern and Southern Bulgaria as follows: for ⁹⁰Sr—1.0 ± 0.5 and 2.3 ± 1.3 kBq/m², ²³⁸Pu—1.3 ± 0.8 and 2.8 ± 1.6 Bq/m², ^239+240Pu—15 ± 14 and 47 ± 38 Bq/m², and ²⁴¹Pu—520 ± 200 and 760 ± 260 Bq/m².     

Synthesis of <Emphasis Type="Italic">O</Emphasis>-[2-[<Superscript>18</Superscript>F]fluoro-3-(2-nitro-1<Emphasis Type="Italic">H</Emphasis>-imidazole-1-yl)propyl]tyrosine ([<Superscript>18</Superscript>F]FNT]) as a new class of tracer for imaging hypoxia

For detection of hypoxic tumor tissue, all radiotracers synthesized until now, are based on the concept that cellular uptake is being controlled by diffusion. As a new approach, we chose the concept to have the tracer hypothetically transported into the cells by well known carrier systems like the amino acid transporters. For this purpose, radiosynthesis of O-[2-[¹⁸F]fluoro-3-(2-nitro-1H-imidazole-1yl)propyl]tyrosine ([¹⁸F]FNT]) was carried out from methyl 2-(benzyloxycarbonyl)-3-(4-3-(2-nitro-1H-imidazol-1-yl)-2-(tosyloxy)propoxy) phenyl)propanoate via no-carrier-added nucleophilic aliphatic substitution. After labelling, 81 ± 0.9% of labelled intermediate i.e. methyl 2-(benzyloxycarbonyl)-3-(4-(2-[¹⁸F]fluoro-3-(2-nitro-1H-imidazole-1-yl)propoxy) phenyl)propanoate was obtained at 140 °C. At the end of radiosynthesis, [¹⁸F]FNT was obtained in an overall radiochemical yield of 40 ± 0.9% (not decay corrected) within 90 min in a radiochemical purity of >98% in a formulation ready for application in the clinical studies for PET imaging of hypoxia.     

Production of <Superscript>122</Superscript>Sb for the study of environmental pollution

This article presents, ¹²²Sb (T _1/2 = 2.723 days, I _β- = 97.59%) was produced via the ^natSn(p,xn) nuclear process at the AMIRS (Cyclone-30, IBA, Belgium). The electrodeposition experiments were carried out by potassium stannate trihydrate (K₂Sn(OH)₆) and potassium hydroxide. The optimum conditions of the electrodeposition of tin were as follows: 40 g/L ^natSn, 20 g/L KOH, 115 g/L K₂Sn(OH)₆, DC current density of 5 A/dm² with a bath temperature of 75 °C. The electroplated Tin-target was irradiated with 26.5 MeV protons at current of 180 μA for 20 min. Solvent extraction of no-carrier-added ¹²²Sb from irradiated Tin-natural target hydrochloric solution was investigated using di-n-butyl ether (C₈H₁₈O). Yields of about 3.61 MBq/μAh were experimentally obtained.     

Cellulase-Producing Bacteria from Thai Higher Termites, <Emphasis Type="Italic">Microcerotermes</Emphasis> sp.: Enzymatic Activities and Ionic Liquid Tolerance

The three highest hydrolysis-capacity-value isolates of Bacillus subtilis (A 002, M 015, and F 018) obtained from Thai higher termites, Microcerotermes sp., under different isolation conditions (aerobic, anaerobic, and anaerobic/aerobic) were tested for cellulase activities—FPase, endoglucanase, and β-glucosidase—at 37 °C and pH 7.2 for 24 h. Their tolerance to an ionic liquid, 1-butyl-3-methylimidazolium chloride ([BMIM]Cl), was also investigated. The results showed that the isolate M 015 provided the highest endoglucanase activity whereas the highest FPase and β-glucosidase activities were observed for the isolate F 018. The isolate F 018 also showed the highest tolerance to [BMIM]Cl in the range of 0.1–1.0 vol.%. In contrast, the isolate A 002 exhibited growth retardation in the presence of 0.5–1.0 vol.% [BMIM]Cl.     

Autoradiolysis of the 2-deoxy-2-[<Superscript>18</Superscript>F]fluoro-D-glucose radiopharmaceutical

Summary To control virtually the toxic compounds and to improve quality control of the solution of 2-deoxy-2-[¹⁸F]fluoro-d-glucose (2-[¹⁸F]FDG), the products of its autoradiolysis were analyzed by high-performance liquid chromatography with electrospray mass spectrometric and radiometric detectors (HPLC/MS/RAD), thin layer chromatography on TLC silica plate and HPTLC on amino modified silica plate. Except Kryptofix^™ 2.2.2, glucose and fluoride anion, no by-products and impurities were observed by LC/MS analysis of fresh 2-[¹⁸F]FDG samples. The analysis performed in the time interval of 6 to 48 hours after the end of 2-[¹⁸F]FDG synthesis indicated that the activity of the autoradiolysis products separated by HPLC did not exceed 1.3%. As the main autoradiolysis products of 3.3 ^. 10^-5 to 4.4 ^. 10^-5M 2-[¹⁸F]FDG solution of original specific activity 0.5-1.5 GBq ^. cm^-3 were established: arabinose - 2.8 μM (G= 0.07/100 eV), gluconic and glucuronic acids 1.8-0.5 μM (G =0.01-0.05/100 eV), arabinose and araburonic acids occurred under 0.5 μM concentration at residual glucose contents about 0.14 mM. Radiation chemical yields of active products were calculated from molar activity of 2-[¹⁸F]FDG and the percentage of their activity: 0.5% radiochemical yield of 2-[¹⁸F]fluoroglucuronic acid corresponds to the G = 0.004/100 eV and 0.3% yield of 2-[¹⁸F]fluorogluconic acid issues G = 0.003/100 eV.     

Separation of no-carrier-added <Superscript>107,109</Superscript>Cd from proton induced silver target: classical chemistry still relevant

The classical chemistry like precipitation technique is relevant even in modern days trans-disciplinary research from the view point of green chemistry. A definite demand of no-carrier-added (nca) cadmium tracers, namely, ^107,109Cd, has been realized for diverse applications. Development of efficient separation technique is therefore important to address the purity of the tracers for various applications. No-carrier-added ^107,109Cd radionuclides were produced by bombarding natural silver target matrix with 13 MeV protons, which gave ~15 MBq/μA h yield for nca ¹⁰⁷Cd. The nca cadmium radionuclides were separated from the natural silver target matrix by precipitating Ag as AgCl. The developed method is an example wherein green chemistry is used in trans-disciplinary research. The method is also simple, fast, cost effective and environmentally benign.     

Determination of <Superscript>151</Superscript>Sm and <Superscript>147</Superscript>Pm using liquid scintillation tracer methods

The long-lived rare earth isotopes ¹⁵¹Sm (90 years, β _max = 76.3 keV) and ¹⁴⁷Pm (2.62 years, β _max = 224.6 keV) are low-yield fission products that generally require lengthy separation procedures to isolate and count by their beta emissions. We will describe novel liquid scintillation counting techniques using radioactive tracers to determine radiochemical yields from an environmental matrix. The recovery of ¹⁵¹Sm is determined from the alpha decay (2.25 MeV) of ¹⁴⁷Sm in the natural Sm carrier and is in excellent agreement with the gravimetric recovery. The ¹⁴⁷Pm recovery is determined by the use of ¹⁴⁵Pm (17.7 years, EC) tracer, custom-produced at LANL using an isotopically enriched target of ¹⁴⁴Sm. We have determined the ¹⁴⁵Pm recovery both from the 37.4 keV k_α1 X-ray, and the electron-capture emissions by LSC. A comparison of these recovery methods is presented.     

Determination of HEPES in <Superscript>68</Superscript>Ga-labeled peptide solutions

A practical and reliable HPLC method was used for the determination of 2-[4-N-(2-hydroxyethyl)-1-piperazinyl]-N′-ethanesulfonic acid (HEPES) content in the ⁶⁸Ga-labeled [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid]-1-Nal3-octreotide (DOTANOC). Linearity of this method was observed in a concentration range of 0.01–10 mg mL⁻¹ and the quantitative limit (signal to noise = 11) was determined as 10 μg mL⁻¹. The HEPES concentration in the final products of ⁶⁸Ga-DOTANOC was typically lower than the detection limit. Pure water and HEPES buffer as reaction medium were investigated using various activities of gallium-68. It was demonstrated that the presence of HEPES buffer consistently furnished very high radiochemical purity of ⁶⁸Ga-DOTANOC, which remained stable for several hours post-labeling. Evidence is provided that in addition to its role as a buffer, HEPES also functions as a radioprotectant agent.     

Radiosynthesis and preliminary biological evaluation of the 2-[<Superscript>18</Superscript>F]fluoropropionic acid enantiomers for tumor PET imaging

The aim of this study was to synthesize the optically pure [¹⁸F]FPA, and to investigate the diagnostic value of different isomers. Semi-automated radiosynthesis of R-[¹⁸F]FPA or S-[¹⁸F]FPA was respectively from the chiral precursor (S)- or (R)-ethyl 2-(((trifluoromethyl)sulfonyl)oxy)propanoate via a two-step reaction and performed on the commercial FDG synthesizer. The improved radiochemical yields of R-[¹⁸F]FPA and S-[¹⁸F]FPA were 30–40% (decay-uncorrected, n = 10) in 35 min. There was no significant difference on the biodistribution of two enantiomers in normal mice (P > 0.05), but positron emission tomography imaging demonstrated that R-[¹⁸F]FPA was more suitable for PC3 tumor imaging than S-[¹⁸F]FPA and [¹⁸F]FDG.     

Cyclotron production of <Superscript>169</Superscript>Yb: a potential radiolanthanide for brachytherapy

In the present study, ytterbium-169 was produced via the ¹⁶⁹Tm(p, n)¹⁶⁹Yb nuclear process at the AMIRS (Cyclone-30, IBA, Belgium) cyclotron, irradiating Tm₂O₃ with proton particles of 15 MeV primary energy and 20 μA current for 20 min. Deposition of Tm₂O₃ on Cu substrate was carried out via by the sedimentation method. The 543 mg of thulium(III)oxide with 108 mg of ethyl cellulose and 8 mL of acetone were used to prepare a Tm₂O₃ layer of 11.69 cm². Yields of about 0.643 MBq ¹⁶⁹Yb per μAh were experimentally obtained. ¹⁶⁹Yb was separated in 80 ± 5% radiochemical yield using liquid–liquid extraction. Solvent extraction of no-carrier-added ¹⁶⁹Yb from irradiated thulium(III)oxide target hydrochloric solution was investigated using di-(2-ethylhexyl)phosphoric acid (HDEHP).     

Modeling β-γ coincidence spectra of <Superscript>131m</Superscript>Xe, <Superscript>133</Superscript>Xe, <Superscript>133m</Superscript>Xe,and <Superscript>135</Superscript>Xe

In support of the Comprehensive Nuclear-Test-Ban Treaty (CTBT), improvements have been made to the model of the Automated Radioxenon Sampler/Analyzer (ARSA) β-γ coincidence detector for radioxenon monitoring. MCNPX is used to simulate the detector response for all the electrons and photons emitted from ^131mXe, ¹³³Xe, ^133mXe, ¹³⁵Xe, and ¹³⁷Cs signals. A MatLab code was written to incorporate the MCNPX results in the calculation of β-γ coincidence spectra. These will aid in the development of the Spectral Deconvolution Analysis Tool (SDAT)¹ and to calibrate β-γ coincidence systems. The models developed for this work include improvements over previous models in their ability to address Compton scattering in the β-cell, and the β-distribution offset in the 31 keV γ-ray region for ¹³³Xe.     

One-step conjugation of glycylglycine with [<Superscript>18</Superscript>F]FDG and a pilot PET imaging study

This study describes a single step conjugation of Glycylglycine (GlyGly) which is a small peptide, with [¹⁸F]FDG via oxime formation. Amiooxy-functionalization of GlyGly (AO-GlyGly) was accomplished through the reaction of Boc-aminooxy succinimide ester. Conjugation reaction was performed at 100 °C for 30 min in a vial containing AO-GlyGly and [¹⁸F]FDG solution. The radiolabeled product ([¹⁸F]FDG-GlyGly) was obtained with 98.65?±?0.35% yield without any purification step which makes this method more attractive for ¹⁸F radiolabeling. The present study is concluded with an in vivo pilot animal PET study to assess biodistribution and kinetics of chemoselectively [¹⁸F]FDG tagged GlyGly in vivo.     

Synthesis of <Emphasis Type="Italic">O</Emphasis>-(2-[<Superscript>18</Superscript>F]fluoroethyl)-<Emphasis Type="Italic">L</Emphasis>-tyrosine and its biological evaluation in B16 melanoma-bearing mice as PET tracer for tumor imaging

O-(2-[¹⁸F]fluoroethyl)-L-tyrosine ([¹⁸F]FET), a fluorine-18 labeled analogue of tyrosine, has been synthesized and biologically evaluated in tumor-bearing mice. The whole synthesis procedure is completed within 50 min. The radiochemical yield is about 40% (no decay corrected) and radiochemical purity more than 97% after simplified solid phase extraction. [¹⁸F]FET shows rapid, high uptake and long retention in the tumor as well as low uptake in the brain. The ratios of tumor-to-muscle (T/M) and tumor-to-blood (T/B) of [¹⁸F]FET are similar to those of [¹⁸F]FDG, but the ratios of tumor-to-brain (T/Br) are 2–3 times higher than that of [¹⁸F]FDG. Autoradiography of [¹⁸F]FET demonstrates a remarkable accumulation in melanoma with high contrast. It appears to be a probable competitive candidate for melanoma imaging with PET. Supported by the Knowledge Innovation Project of Chinese Academy of Sciences (No. KJCX1-SW-08) and the National Natural Science Foundation of China (Grant No. 30371634)     

Development of <Superscript>177</Superscript>Lu-DOTA-anti-CD20 for radioimmunotherapy

Rituximab was successively labeled with ¹⁷⁷Lu-lutetium chloride. ¹⁷⁷Lu chloride was obtained by thermal neutron flux (4 × 10¹³ n cm⁻² s⁻¹) of natural Lu₂O₃ sample with a specific activity of 2.6–3 GBq/mg. The macrocyclic bifunctional chelating agent, N-succinimidyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA-NHS) was prepared at 25 °C using DOTA, N-hydroxy succinimide (NHS) in CH₂Cl₂. DOTA-rituximab was obtained by the addition of 1 mL of a rituximab pharmaceutical solution (5 mg/mL, in phosphate buffer, pH 7.8) to a glass tube pre-coated with DOTA-NHS (0.01–0.1 mg) at 25 °C with continuous mild stirring for 15 h. Radiolabeling was performed at 37 °C in 24 h. Radio-thin layer chromatography showed an overall radiochemical purity of >98% at optimized conditions (specific activity = 444 MBq/mg, labeling efficacy; 82%). The final isotonic ¹⁷⁷Lu-DOTA-rituximab complex was checked by gel electrophoresis for structure integrity control. Radio-TLC was performed to ensure that only one species was present after filtration through a 0.22 μm filter. Preliminary biodistribution studies in normal rats were carried out to determine complex distribution of the radioimmunoconjugate up to 168 h. The biodistribution data were in accordance with other antiCD20 radioimmunoconjugates already reported.     

Targetry and specification of <Superscript>167</Superscript>Tm production parameters by different reactions

In recent years, there has been a rapid expansion in the use of radio nuclides for therapeutic purposes. Thulium–167 is an important radionuclide (T _1/2 = 9.25 d) due to it could be used for tumor and bone studies in nuclear medicine. ¹⁶⁷Tm complexed with hydroxy ethylene diamine tetra-acetic acid (HEDTA) could be used with the aim of bone imaging. ¹⁶⁷Tm emits a prominent γ ray of 208 keV energy and low energy electrons. This study describes calculations on the excitation functions of ¹⁶⁵Ho(α,2n)¹⁶⁷Tm, ¹⁶⁷Er(p,n)¹⁶⁷Tm, ^natEr(d,xn)¹⁶⁷Tm and ^natEr(p,xn)¹⁶⁷Tm reactions by ALICE/ASH (hybrid and GDH models) and TALYS-1.0 codes. In addition, calculated data by codes were compared to experimental data that earlier were published and TENDL-2010 database. Moreover, optimal thickness of the targets and physical yield were obtained by SRIM (stopping and range of ions in matter) code for each reaction. According to the results, the ¹⁶⁷Er(p,n)¹⁶⁷Tm and ¹⁶⁵Ho(α,2n)¹⁶⁷Tm reactions are suggested as the best method to produce ¹⁶⁷Tm owing to minimum impurities. The TALYS-1.0 code, predict the maximum cross-section of about 382 mb at 11 MeV and 849 mb at 26 MeV for ¹⁶⁷Er(p,n)¹⁶⁷Tm and ¹⁶⁵Ho(α,2n)¹⁶⁷Tm reactions, respectively. Finally, deposition of ^natEr₂O₃ on Cu substrate was carried out via the sedimentation method. The 516 mg of erbium(III)oxide with 103.2 mg of ethyl cellulose and 8 mL of acetone were used to prepare a ^natEr₂O₃ layer of 11.69 cm². ¹⁶⁷Tm was produced via the ^natEr(p,n)¹⁶⁷Tm nuclear process at 20 μA current and 15 → 7 MeV protons beam (1 h). Yield of about 3.2 MBq ¹⁶⁷Tm per μA h were experimentally obtained.