A novel electrochemical <Superscript>99</Superscript>Mo/<Superscript>99m</Superscript>Tc generator

A novel electrochemical process to avail clinical grade ^99mTc from (n,γ)⁹⁹Mo has been demonstrated. The electrochemical parameters were optimized to maximize the ^99mTc yield with minimal ⁹⁹Mo contamination. ⁹⁹Mo/^99mTc generators containing up to 29.6 GBq (800 mCi) ⁹⁹Mo were developed and their performance were extensively evaluated for 10 days without changing the operating conditions. Very high radioactive concentration of ^99mTcO₄ ⁻ of acceptable quality, commensurate with hospital radiopharmacy requirements could be availed from the system with >90% yield. The compatibility of the product for the formulation of ^99mTc labeled radiopharmaceuticals such as ^99mTc-DMSA and ^99mTc-EC was found to be satisfactory in terms of high labeling yields. The proposed route represents an important step for enhancing the scope of accessing clinical grade ^99mTc from low specific activity (n, γ)⁹⁹Mo.     

Determination of radionuclidic impurities in <Superscript>99m</Superscript>Tc eluate from <Superscript>99</Superscript>Mo/<Superscript>99m</Superscript>Tc generator for quality control

Technetium-99m is the principal radioisotope used in medical diagnostics; radionuclidic impurity is the major concern of its quality. This work presents a analytical method for sequential determination of all radionuclidic impurities listed in pharmacopoeia including gamma emitters, alpha emitters, ⁸⁹Sr and ⁹⁰Sr. Radioactive decay for removal of ^99mTc, ion exchange and extraction chromatography for removal of ⁹⁹Mo and ⁹⁹Tc are effective for separation of interferences. Gamma spectrometry, LSC with alpha/beta discrimination, and Cherenkov counting using LSC are sensitive methods for measurement of the impurity radionuclides. The detection limits of this method are well meet the requirement of the quality control according to the limitation of the pharmacopoeia.     

The interaction of <Superscript>99m</Superscript>Tc with pyrimidine compounds

The reaction of ^99mTc of different oxidation states (+7, +4) with 2-thiouracil and 5-nitrobarbituric acid have been studied at different temperatures, pH and concentrations. The reaction mixtures have been analyzed at different times using thin layer chromatography (TLC) and a radio detector to show the peaks at the plates. ^99mTc is obtained from the Mo generators with oxidation state (+7). The use of SnCl₂ as a reducing agent gave ^99mTc with oxidation state (+4). It is very difficult to separate the complexes formed from the reactions in very small concentration. The percentage of ^99mTc and its oxidation state involved in the complexes can be determined. The labeling efficiencies (percentage of complex) in the reaction of ^99mTc⁺⁷ with 5-nitro-barbituric-acid increases mostly at pH  10. Both oxidation states of ^99mTc(+7, +4) can be detected at pH’s 4 and 10, but at pH  4, the reduced form ^99mTCO₂, is more pronounced. At pH  7 no complexes were detected and most of ^99mTc remains as ^99mTCO₄ ⁻ . By increasing the ligand concentration, the labeling efficiencies of the complex increases. For the reaction of ^99mTc of oxidation states (+4, +7) with 2-thiouracil at different temperatures and analytical times it is concluded that several complexes with different R_f values were observed in equilibrium and most of these complexes were unstable.     

Synthesis and biological evaluation of <Superscript>99m</Superscript>Tc labeled aryl piperazine derivatives as cerebral radiotracers

The aim of this study is to develop cerebral radiotracers for central nervous system receptors imaging. The synthesis, characterization and biological evaluation of two aryl piperazine ^99mTc-radiocomplexes based on the piano stool motif [CpM(CO₃)] (Cp = cyclopentadienyl, M = ^99mTc/Re) is reported. The ^99mTc-radiocomplexes were obtained quickly (time < 5 min) with high radiochemical yields. The ^99mTc-radiocomplexes characterized by high performance liquid chromatography comparison with the rhenium surrogates have both a suitable lipophilicity and are able to cross the blood brain barrier with 0.43 ± 0.05 and 1.96 ± 0.06% ID/g of brain uptake, at 10 min post injection.     

<Superscript>99</Superscript>Mo/<Superscript>99m</Superscript>Tc generators based on aluminum molybdate gel matrix prepared by nano method

A procedure for preparation of ⁹⁹Mo/^99mTc radioisotope generator based on low specific activity neutron activated ⁹⁹Mo was developed. Aluminum molybdate(VI)-⁹⁹Mo of high Mo(VI) content (~?364 mg/g Al⁹⁹Mo) was prepared by mixing low specific activity molybdate(VI)-⁹⁹Mo and aluminum mixture solution with isoamyl alcohol. Al⁹⁹Mo gel matrix was precipitated when the pH of the mixture solution was raised to ~?5 by addition of NaOH to the mixture. Radiometric measurements indicate the strong fixation of Molybdate(VI)-⁹⁹Mo species in the form of the sparingly insoluble Al⁹⁹Mo gel matrix. The prepared AlMo gel matrix was physiochemically characterized. Al⁹⁹Mo gel matrix was used as a base material for preparation of ⁹⁹Mo/^99mTc generator. The ^99mTc eluted from ⁹⁹Mo/^99mTc radioisotope generator was found to have relatively high elution yield (84?±?2.3%), radionuclidic (≥?99.99%), radiochemical (98.1?±?0.9%) and chemical purity.     

Synthesis and evaluation of a new bombesin analog labeled with <Superscript>99m</Superscript>Tc as a GRP receptor imaging agent

Tumors such as prostate, small cell lung cancer, breast, gastric and colon cancer are known to overexpress receptors to bombesin (BBN). In this study, a new bombesin analogue was labeled with ^99mTc via HYNIC and tricine/EDDA as coligands and investigated further. HYNIC-GABA-Bombesin (7–14) NH₂ was synthesized using a standard Fmoc strategy. Labeling with ^99mTc was performed at 100 °C for 10 min and radiochemical analysis involved ITLC and HPLC methods. The stability of radiopeptide was checked in the presence of humane serum at 37 °C up to 24 h. The receptor bound internalization and externalization rates were studied in GRP receptor expressing PC-3 cells. Biodistribution of radiopeptide was studied in nude mice bearing PC-3 tumor. Labeling yield of >98% was obtained corresponding to a specific activity of ~2.6 MBq/nmol. Peptide conjugate showed good stability in the presence of human serum. The radioligand showed high and specific internalization into PC-3 cells (14.63 ± 0.41% at 4 h). In biodistribution studies, a receptor-specific uptake was observed in GRP-receptor-positive organs so that after 4 h the uptakes in mouse tumor and pancreas were 1.31 ± 0.18 and 1.2 ± 0.13% ID/g, respectively.     

Combined determination of <Superscript>99</Superscript>Tc and <Superscript>108m</Superscript>Ag in L/ILW liquid wastes

The low- and intermediate-activity level liquid wastes produced by the Paks Nuclear Power Plant (NPP) contain routinely measureable gamma-emitting (e.g., ⁵⁴Mn, ⁶⁰Co, ^110mAg, and ¹³⁷Cs) as well as many so-called “difficult-to-measure” radionuclides. Despite of their low specific activity compared to the total, the reliable determination of these radionuclides is an important issue of nuclear waste management. The increasing amount of waste samples to be qualified yearly by our laboratory put a pressure on revising the existing procedure of ⁹⁹Tc separation applied. We have managed to halve the initial amount of the sample required to achieve the same level of detection of technetium. Furthermore, one of the new purifying steps introduced have proved to be able to separate ^108mAg (and ^110mAg) better than 99% keeping the ⁹⁹Tc content of the product almost intact. Means of separation of ⁹⁹Tc from ¹⁰⁶Ru and ^124+125Sb have also been successfully investigated. As intended, this new procedure has a major impact on the chemical reagent as well as the electricity requirement of the separation making it more cost-effective.     

Study of magnetic ferrite nanoparticles labeled with <Superscript>99m</Superscript>Tc-pertechnetate

This study examined the applications of novel non-polymer magnetic ferrite nanoparticles (Fe₃O₄ NPs) labeled with ^99mTc-pertechnetate (^99mTcO₄ ⁻). The radiochemistry, chemistry, and biodistribution of Fe₃O₄ NPs labeled with ^9mTcO₄ ⁻ were analyzed. This paper employed instant thin layer chromatography and magnetic adsorption to evaluate the labeling efficiency and stability of ^99mTc-Fe₃O₄ at various reaction conditions. A scanning electron microscope, X-ray diffractometer, Fourier transform infrared spectrometer, laser particle size analyzer, and superconducting quantum interference device magnetometer were used to analyze the physical and chemical properties of the Fe₃O₄ and ⁹⁹Tc-Fe₃O₄ nanoparticles. The biodistribution and excretion of ^99mTc-Fe₃O₄ were also investigated. Radiochemical analyses showed that the labeling efficiency was over 92% after 1 min in the presence of a reducing agent. Hydroxyl and amine groups covered the surface of the Fe₃O₄ particles. Therefore, ⁹⁹Tc (VII) reduced to lower oxidation states and might bind to Fe₃O₄ NPs. The sizes of the ⁹⁹Tc-Fe₃O₄ NPs were about 600 nm without ultrasound vibrations, and the particle sizes were reduced to 250 nm under ultrasound vibration conditions. Nonetheless, Fe₃O₄ NPs and ⁹⁹Tc-Fe₃O₄ NPs exhibited superparamagnetic properties, and the saturation magnetization values were about 55 and 47 emu/g, respectively. The biodistribution showed that a portion of the ^99mTc-Fe₃O₄ nanoparticles might embolize in a pulmonary capillary initially; the embolism radioactivity was cleared from the lungs and was then taken up by the liver. ^99mTc-Fe₃O₄ metabolized very slowly only 1–2% of the injected dose (ID) was excreted in urine and about 2.37% ID/g was retained in the liver 4 h after injection. Radiopharmaceutically, ^99mTc-Fe₃O₄ NPs displayed long-term retention, and only ^99mTc-Fe₃O₄ NPs that dissociated to free pertechnetate could be excreted in urine. This research evaluated the feasibility of non-polymer magnetic ferrite NPs labeled with technetium as potential radiopharmaceuticals in nuclear medicine.     

Activity standardization of <Superscript>99m</Superscript>Tc using liquid scintillation counting method

The Korea Research Institute of Standards and Science (KRISS) participated in the BIPM.RI(II)-K4.Tc-99 m comparison of activity measurements of ^99mTc. We develop the national primary standard for ^99mTc solution used during the comparison. We use two primary liquid scintillation counting techniques for the standardization: digital coincidence counting with the 4πβ(LS)-γ(NaI(T1))system and triple-to-double coincidence ratio counting. Both methods give consistent results for the specific activity of a ^99mTc solution. Adopting the result from the DCC method as the reference value of the ^99mTc measurement, we evaluate the standard uncertainty of 0.856% for the KRISS primary standard of the ^99mTc activity. The K4 comparison result shows that the newly-established KRISS primary standard lies within the standard uncertainty with the key comparison reference value defined from other ^99mTc measurements.     

Global fallout levels of <Superscript>99</Superscript>Tc and activity ratio of <Superscript>99</Superscript>Tc/<Superscript>137</Superscript>Cs in the Pacific Ocean

Summary Global fallout levels of ⁹⁹Tc and ¹³⁷Cs of surface seawater in the Pacific Ocean were measured. The ⁹⁹Tc concentrations ranged from 0.62 to 3.33 mBq^. m^-3and 5 of 6 samples showed less than 1 mBq^. m^-3except one sample taken in the Great Barrier Reef, Australia. The ¹³⁷Cs concentrations ranged from 2.13 to 3.14 Bq^. m^-3, showing a gradual decrease in the North Pacific toward the equator and a constant level in the South Pacific. The ⁹⁹Tc/¹³⁷Cs activity ratios ranged from 2.5^. 10^-4to 2.9^. 10^-4, which is very close to that calculated theoretically from the fission yield.     

Evaluation of fresh and old eluate of <Superscript>99</Superscript>Mo/<Superscript>99m</Superscript>Tc generators used for labeling of different pharmaceutical kits

Summary Sixty ⁹⁹Mo/^99mTc wet column generators, loaded with two different ⁹⁹Mo activities, were analyzed in order to assess the quality of their eluates. Each elution was used for labeling of different radiopharmaceuticals, in order to evaluate whether “risky” elutions, namely those performed just after generator delivery and at 72 hours or more from the last elution, could be conveniently employed when fresh available radioactivity is not enough for the planned labeling or when shipping problems arise, or delay in delivery of a new generator occurs. Radiochemical quality control of all radiopharmaceuticals labeled with these elutions was performed. The elutions differed mainly in ⁹⁹Tc ground state (^99gTc) and amounts of oxidizing impurities. Radiolabeling procedures, however, were not affected, suggesting that these “risky” elutions might be appropriately used, in “emergency” conditions, for labeling radiopharmaceuticals although their radiochemical purity control is recommended prior to patient administration.     

Labelling of peptides with <Superscript>99m</Superscript>Tc complexes through the modified C-terminal group

Easy and efficient way to modify of the C-terminus of the peptide using amino acid lysine has been proposed and experimentally verified. The synthesis yield was high (≥85%) and it was found that reactions can be carried out even with microgram amounts of the peptide. Using Fmoc-alanine (as the peptide model) with modified C-terminus the procedure of peptide labelling with monovalent and trivalent ^99mTc complexes has been elaborated.     

Synthesis of <Superscript>131</Superscript>I labeled estrone derivatives and biodistribution studies on rats

Summary The aim of this study is to synthesize novel ¹³¹I labeled estrone derivatives that may have therapeutical potentials on Estrogen Receptor rich tumors. Two radiolabeled estrone derivatives, [¹³¹I]2-iodo-3-methoxy-estra-1,3,5-trien-17-one and [¹³¹I]4-iodo-3-methoxy-estra-1,3,5-trien-17-one were synthesized. Ether amino estrone derivatives were obtained from estrone in three steps by means of diazonium compounds. Tissue distribution studies exhibited receptor-mediated uptake in target organs in female Albino Wistar rats. Maximum uptakes for 2-iodo[¹³¹I]-3-methoxy-estrone are in stomach, pancreas, intestines and uterus. A similar biodistribution profile was obtained for 4-iodo[¹³¹I]-3-methoxy-estrone. However 2-iodo-3-methoxy-estra-1,3,5-trien-17-one has higher uptake in stomach, kidneys, pancreas, and intestines than 4-iodo-derivative.     

Structural determination of <Superscript>99</Superscript>Tc radiopharmaceuticals and compounds using X-ray absorption spectroscopy

Summary ^99mTc compounds play a very important role in modern medicine. These compounds are among the most widely used radiopharmaceuticals. Unfortunately, due to the necessity of working with small quantities of materials, the chemistry of these materials is not completely understood. Currently, the structure of the ^99mTc-DTPA (a common renal imaging agent) is unknown. In this paper, we show that X-ray absorption spectroscopy (XAS) can be used to determine the structure of Tc ycompounds b comparing XAS results to those from X-ray diffraction (XRD). Specifically, XAS data and fits for TcCl₆^2-, TcOCl_4-, and TcNCl_4- were found to be in excellent agreement with the known structures from XRD. Finally, we show the XAS spectrum from a 77 ng sample of ⁹⁹Tc-DTPA. To our knowledge this is the first XAS spectrum taken from this material. The near-edge region (XANES) was visible after a single scan on this material. This clearly indicates that we will be able to determine the local atomic structure of this material.     

Preparation and biodistribution in mice of <Superscript>99m</Superscript>Tc-DTPA-b-cyanocobalamin

Summary Cyanocobalamin (CNCbl), a kind of vitamin B12 (cobalamin, Cbl), which has a special binding capability to rapid dividing cells and proliferating tissue, especially tumors, has been modified and labeled by ^99mTc. The optimal labeling condition was determined, and the biodistribution of ^99mTc-DTPA-b-CNCbl both in normal mice and TA₂ mice bearing MA891 mammary tumors were studied. ^99mTc-DTPA-b-CNCbl showed low uptake and rapid clearance in nontarget tissues, and renal excretion. About 40% of uptake at 1 hour remained in the tumor at 12 hours p.i. The satisfying ratio of T/NT was acquired at 6 hours p.i.     

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.     

Labeling bombesin-like peptide with <Superscript>99m</Superscript>Tc via hydrazinonicotinamide: description of optimized radiolabeling conditions

Bombesin (BNN)-like peptides have very high binding affinity for the gastrin-releasing peptide (GRP) receptor. The goal of the current study was to optimize the labeling conditions of a new ^99mTc-radiolabeled BNN-like peptide based on the bifunctional chelating ligand HYNIC using different co-ligands (EDDA and tricine). The radiolabeling conditions (pH, amount of co-ligand, amount of stannous chloride, temperature and reaction time) for newly-formed ^99mTc-tricine-HYNIC-Q-Litorin and ^99mTc-EDDA-HYNIC-Q-Litorin were optimized and evaluated by RHPLC and RTLC. Radiochemical yields for ^99mTc-tricine-HYNIC-Q-Litorin and ^99mTc-EDDA-HYNIC-Q-Litorin were 98.0 ± 1.7 and 97.5 ± 2.5%, respectively. When EDDA was used as co-ligand, the labeling of ^99mTc-EDDA-HYNIC-Q-Litorin was optimal in the following reaction mixture: HYNIC-peptide: EDDA: 10 μg/5 mg, pH 3, SnCl₂ concentration: 12 μg/0.1 mL, reaction temperature: 100 °C, reaction time: 15 min. Besides, the optimum conditions were HYNIC-peptide:tricine: 10 μg/50 mg, pH 5, SnCl₂ concentration: 12 μg/0.1 mL, reaction temperature: 100 °C, reaction time: 15 min for preparing ^99mTc-tricine-HYNIC-Q-Litorin. The manufactured ^99mTc-HYNIC-Q-Litorin conjugates may offer new possibilities for imaging cancer cells expressing bombesin receptors.     

Effect of humic acid on the sorption of technetium on hematite colloids using <Superscript>95m</Superscript>Tc and <Superscript>96</Superscript>Tc as tracers

Sorption of technetium on hematite colloids, at varying pH (3–10), has been studied in absence and presence of humic acid using ^95mTc-⁹⁶Tc radiotracers. Technetium was found to be weakly sorbed on hematite at lower pH (<5) values, while no sorption was observed at higher pH values. Humic acid was found to have no effect on the sorption of technetium on hematite under aerobic conditions, while at lower pH values small reduction was observed which was attributed to the reduced zeta potential of the hematite colloids owing to the strong sorption of humic acid.     

Preparation of <Superscript>99m</Superscript>Tc-PQQ and preliminary biological evaluation for the NMDA receptor

Pyrroloquinoline quinone (PQQ), an essential nutrient, antioxidant, redox modulator and nerve growth factor found in a class of enzymes called quinoproteins, was labeled with ^99mTc by using stannous fluoride (SnF₂) method. Radiolabeling qualification, quality control and characterization of ^99mTc-PQQ and its biodistribution studies in mice were performed and discussed. Effects of pH values, temperature, time and reducing agents concentration on the radiolabeling yield were investigated. The quality control procedure of ^99mTc-PQQ was determined by thin layer chromatography (TLC), radio high-performance liquid chromatography (RHPLC) and paper electrophoresis methods. The average radiolabeling yield was 94 ± 1% under optimum conditions of 0.99 mg of PQQ, 30 μg of SnF₂, 0.5 mg of ethylenediaminetetraacetic acid disodium salt (EDTA-2Na) and 18.5 MBq of Na^99mTcO₄ at pH 6 and 25 °C with a response volume of 1 ± 0.1 mL. ^99mTc-PQQ was stable and anionic. Lipid–water partition coefficient of ^99mTc-PQQ was −1.49 ± 0.16. The pharmacokinetics parameters of ^99mTc-PQQ were t _1/2α = 18.16 min, t _1/2β = 100.45 min, K ₁₂ = 0.013 min⁻¹, K ₂₁ = 0.017 min⁻¹, K _e = 0.016 min⁻¹, AUC (area under the curve) = 1040.78 ID% g⁻¹ min and CL (plasma clearance) = 0.096 mL min⁻¹. The dual-exponential equation was Y = 10.88e^−0.038t  + 5.21e^−0.0069t . The biodistribution of ^99mTc-PQQ was studied in ICR (Institute for Cancer Research 7701 Burhelme Are., Fox Chase, Philadelphia, PA 1911 USA) mice. In vitro autoradiographic studies clearly showed that the ^99mTc-PQQ radioactivity accumulated predominantly in the hippocampus and cortex, which had a high density of N-methyl-d-aspartate Receptor (NMDAR). The enrichment can be blocked by NMDAR redox modulatory site antagonists-ebselen (EB) and ^99mTc-PQQ is therefore a promising candidate for the molecular imaging of NMDAR. To date, however, there have been no studies characterizing ^99mTc-PQQ.