Preparation of 99Mo/99mTc generator based on alumina 99Mo-molybdate (VI) gel

In this work alumina ⁹⁹Mo-molybdate (VI) gel is evaluated as a column matrix for use in the preparation of small chromatographic column type ^99mTc generator. Alumina molybdate (VI) gel is prepared by dissolving inactive MoO₃ with aluminum foil in 5 M NaOH solution containing ⁹⁹Mo radiotracer. After complete dissolution, 0.5 H₂O₂ was added to the reaction mixture solution and acidified to pH 5.5 with concentrated HNO₃. The formed AlMo precipitate was washed with NaNO₃ solution, dried at 50 °C for 24 h and then packed in the form of a chromatographic column for elution of the generated ^99mTc radionuclide with physiological saline solution (0.9 % NaCl). Greater than 86 % of the generated ^99mTc activity is immediately and reproducibly eluted with passing 10 mL of the saline solution through 2.0 g of alumina ⁹⁹Mo-molybdate column bed at a flow rate of about 1.0 mL/min. The high radiochemical ≥98.6 % TcO₄ ^?, radionuclidic ≥99.90 % ^99mTc and chemical purities of the eluates satisfy the specifications for use in nuclear medicine.     

Re-emergence of the important role of radionuclide generators to provide diagnostic and therapeutic radionuclides to meet future research and clinical demands

Radionuclide generators have been the main stay of diagnostic nuclear medicine and it is no exaggeration to state that the growth of nuclear medicine would not have happened to the present levels but for the availability of ⁹⁹Mo/^99mTc generator. This article provides a brief account of the various radionuclide generators currently in clinical use or which have made substantial progress or likely to be materialized in the foreseeable future to bring evolutional progress in nuclear medicine. Further, a brief outline on the regulatory challenges and impact on radionuclide generator technology with the emergence of professionally run central radiopharmacies have been provided.     

Views on quality tests of radiopharmaceuticals

The quality tests of radionuclides produced from generators (⁹⁹Mo→^99mTc,¹¹³Sn→^113mIn) have been reviewed. The quality controls of radiopharmaceuticals derived from these radionuclides and prepared with the help of ready-for-use reagents assembled in kits have been presented. The possibility of new tests regarding sterility (by means of a radiometric method) and detection of endotoxin (based on gelification of limulus amoebocyte lysate) have been suggested.     

Radiostrontium separation from sodium molybdate solution and its measurement using LSA: an application to radiopharmaceutical analysis

Technetium (^99mTc), a decay product of molybdenum (⁹⁹Mo), is employed as radioisotope in nuclear medicine. Several practical devices known as generators are commercially available which enable the user to separate the daughter from the parent radionuclide. The present study is focused on quality control of chromatographic technetium generator. A properly constructed generator should comply with international requirements of radionuclide purity of ⁹⁰Sr/⁹⁹Mo ≤ 6 × 10^?8 and ⁸⁹Sr/⁹⁹Mo ≤ 6 × 10^?7. For this purpose an analytical method was optimized to quantify radiostrontium (⁸⁹Sr and ⁹⁰Sr) in sodium molybdate [Na ₂ ⁹⁹ MoO₄] solution, a fission product used for ⁹⁹Mo/^99mTc generators. Dowex 1 × 8 and alumina were used in sequence followed by tributyl phosphate extraction for radiostrontium separation. Cerenkov measurement of ⁸⁹Sr and ⁹⁰Sr (through its descendent ⁹⁰Y) was performed using Perkin Elmer Tricarb LSA 3170 with detection efficiency of 42 and 14 %, respectively. Since efficiency of Cerenkov counting is sensitive to presence of color, spectral index of sample was used to correct the counting efficiency. The chemical recovery for strontium was 22 % and for yttrium was 80 % as determined by inductively coupled plasma optical emission spectrometry. Lower limit of detection was found to be 6.3 and 14.4 Bq L^?1 for ⁹⁰Sr and ⁸⁹Sr, respectively with 60 min counting time. Hence method can be applied successfully to analyze ^89,90Sr in fission molybdenum used as radiopharmaceutical with a relative error of <10 %.     

Preparation,molecular modeling and biodistribution of 99mTc-phytochlorin complex

Phytochlorin [21H, 23H-Porphine-7-propanoicacid, 3-carboxy-5-(carboxymethyl)13-ethenyl-18-ethyl-7,8-dihydro-2,8,12,17-tetramethyl-,(7S,8S)] was labeled with ^99mTc and the factors affecting the labeling yield of ^99mTc-phytochlorin complex were studied in details. At pH 10, ^99mTc-phytochlorin complex was obtained with a high radiochemical yield of 98.4 ± 0.6 % by adding ^99mTc to 100 mg phytochlorin in the presence of 75 μg SnCl₂·2H₂O after 30 min reaction time. The molecular modeling study showed that the structure of ^99mTc-phytochlorin complex presents nearly linear HO–Tc–OH unit with an angle of 179.27° and a coplanar Tc(N1N2N3N4) unit. Biodistribution of ^99mTc-phytochlorin complex in tumor bearing mice showed high T/NT ratio (T/NT = 3.65 at 90 min post injection). This preclinical study showed that ^99mTc-phytochlorin complex is a potential selective radiotracer for solid tumor imaging and afford it as a new radiopharmaceutical suitable to proceed through the clinical trials for tumor imaging.     

Precision measurements of the half-lives of60mCo,79mSe,104mRh,149Nd,176mLu,177Lu and198Au

Carrier-free^99mTcO₄ ^– eluated from clinical⁹⁹Mo/^99mTc generators was examined to determine its specific activity. The observed specific activity was found to be always lower than the calculated value based on the⁹⁹Mo–^99mTc–⁹⁹Tc decay scheme data. These results could be explained in terms of existence of excess Tc loaded onto generator column.     

Pharmaceutical grade sodium [99mTc] pertechnetate from low specific activity 99Mo using an automated 99Mo/99mTc-TCM-autosolex generator

Performance study of a computer controlled automated closed cyclic module for the separation and recovery of ^99mTc from low specific activity (n, γ) ⁹⁹Mo using methyl ethyl ketone (MEK) solvent extraction technique named ⁹⁹Mo/^99mTc-TCM-AUTOSOLEX (Technetium automated solvent extraction) Generator is described. The entire system is automated and controlled by a user-friendly PC based graphical user interface that actually supervises process via an embedded system based electronic controller. The average yield of separation of ^99mTc was above 85 % and ⁹⁹Mo breakthrough in ^99mTc pertechnetate was <0.002 %. The sodium pertechnetate obtained was a clear solution having pH 6–7, Radiochemical (RC). Purity >99 %, MEK content <0.1 % (v/v), Al and Mo content <10 µg/ml. R. C. Purity of ^99mTc-radiopharmaceuticals studied was not less than 96 %. Bio-Quality control studies confirm that sodium pertechnetate obtained was sterile and pyrogen free. Imaging studies in animals and humans with limited radiopharmaceuticals show that the quality of ^99mTc-pertechenate obtained in the present module was good enough to do clinical study.     

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.     

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.     

Comparison of activity measurements in nuclear medicine services in the Czech Republic

Radionuclide calibrator used in nuclear medicine is the radiation detection equipment for measuring radiopharmaceutical activity. This instrument consists of an ionization chamber with an electrometer. This paper examines the variation in the amounts of radioactivity that is associated with dose calibration. The amount of radioactivity in each sample was measured by CMI and compared with values obtained from radionuclide calibrators over a year period. Measurements of serum bottles were within 10 % for ¹⁸F and ⁹⁰Y, 10–15 % for ¹³¹I and ⁵¹Cr, 10–20 % for ^99mTc, 15–20 % for ⁶⁷Ga, 10–25 % for ¹¹¹In, 15–30 % for ²⁰¹Tl and 15–45 % for ¹²³I.     

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.     

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.     

Comparison of the radiopharmaceutical potentials of dithizone radiolabeled with 131I and with 99mTc

In this study, dithizone (diphenylthiocarbazone) has been separately radiolabeled with ¹³¹I and with ^99mTc for preliminarily testing their radiopharmaceutical potentials on male albino rabbits. ¹³¹I-dithizone and ^99mTc-dithizone were intravenously injected to rabbits via their ear veins after anesthetizing with a mixture of Alfazyne and Alfamine (Serva) to determine their dynamic and static statuses in the metabolism. Also, ^99mTc as pertechnetate and ¹³¹I as iodate were administered to rabbits as controls. Dynamic and static scintigrams were obtained using a gamma camera (Diacan Instruments). Dynamic scintigrams were obtained over the first half hour with frames of 1 minute following the administrations of the labeled compounds. Static images were obtained from posterior projection at different time intervals up to about 3 hours following the administration of the radiolabeled compounds. ^99mTc-dithizone was significantly uptaken by the pancreas in contrast to free ^99mTc. In the case of ¹³¹I-dithizone, the distribution of ¹³¹I activity in the metabolism was clearly different than the case of free ¹³¹I and the uptake of ¹³¹I-dithizone at the pancreas zone was also significant. These preliminary tests have clearly indicated that especially ^99mTc-dithizone has a significant potential to be used as a pancreatic radiopharmaceutical.     

Preparation of radioiodinated ritodrine as a potential agent for lung imaging

Ritodrine (a beta-2 adrenergic receptor agonist) was successfully labeled with ¹²⁵I via direct electrophilic substitution reaction at ambient temperature. ¹²⁵I-ritodrine was obtained with a maximum labeling yield of 97 ± 0.163 % and in vitro stability up to 24 h. Biodistribution studies showed that maximum in vivo uptake of ¹²⁵I-ritodrine in lungs was 20.4 ± 0.22 % injected activity/g tissue at 1 h post-injection, whereas the clearance from mice appeared to proceed mainly via the renal pathway. ¹²⁵I-ritodrine is not a blood product and so it is more safe than the currently available ^99mTc-MAA, and its lung uptake is higher than that of the recently discovered ^99mTc(CO)₅I and ^99mTc-DHPM. As a conclusion, radioiodinated ritodrine could be used as a novel radiopharmaceutical for lung perfusion scan safer than the currently available ^99mTc-MAA and more potential than the recently discovered ^99mTc(CO)₅I and ^99mTc-DHPM.     

A simple and sensitive separation technique of 99Mo and 99mTc from their equilibrium mixture

The present work describes a simple and inexpensive separation method of ⁹⁹Mo from the equilibrium mixture. The liquid–liquid extraction technique has been employed to separate ⁹⁹Mo and ^99mTc using triisooctylamine (TIOA). The ⁹⁹Mo and ^99mTc were quantitatively separated out in 2 M TIOA with tripled distilled water; ^99mTc was back extracted from TIOA organic phase to aqueous phase by 0.1 M DTPA. The species information or indirect speciation of molybdenum was also established by the extraction profile of the molybdenum.     

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.     

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.     

Preliminary studies of 99mTc-PQQ-NMDAR binding and effect of specificity binding by mannitol

Pyrroloquinoline quinone (PQQ) is a powerful neuroprotectant that specifically binds to brain NMDA receptors and inhibits excitotoxicity. Imaging this binding reaction in the brain remains a long sought goal in this field of study, and one of the primary challenges remaining is enabling soluble labeled PQQ to pass the blood–brain barrier (BBB). Previously, our group successfully labeled PQQ with Technetium-99m (^99mTc), a metastable nuclear isomer used in radioactive isotope medical tests. In this work, we determined the specific binding of ^99mTc-PQQ and NMDAR by radioligand receptor assay. Ebselen (EB) and MK-801 both effectively inhibited ^99mTc-PQQ binding. We then investigated methods of opening the BBB using mannitol to enable entry to the brain by ^99mTc-PQQ. Our results showed that 7.5 mL/kg of 20 % mannitol effectively opened the BBB and 20 min was the optimum treatment time. Competition studies showed that mannitol did not affect the specific binding between ^99mTc-PQQ and NMDA receptors. Using this method, the amount of ^99mTc-PQQ uptake and retention was increased most significantly in the hippocampus and cortex, and re-opening the BBB did not affect binding. Together, our results demonstrate that the use of mannitol to open the BBB may contribute significantly to improving image quality by increasing the uptake amount of a water-soluble agent in brain.     

Airborne gamma-ray emitters from Fukushima detected in New York State

An air-sampling network that operates continuously as part of New York State’s environmental surveillance program collected radionuclides emitted as a result of the Fukushima nuclear accident. Samples were collected, typically for 7 days each, by drawing ~600 m³ of air through a particulate-collecting filter followed in series by a canister containing activated charcoal. Additional air sampling was implemented at ~3-day intervals at two locations. Gamma-ray spectroscopy was used to confirm the detection of ¹³¹I, ¹³⁷Cs, ¹³⁴Cs, and ⁷Be in the particulate phase at all sites, with maximum concentrations near 1,260, 160, 160, and 5,200 μBq/m³, respectively. Gas-phase ¹³¹I, collected on activated charcoal, exhibited a maximum concentration of 3,400 μBq/m³ at the sites. Assessment of radionuclide levels in the air samples suggests that there were minimal health impacts from the airborne radionuclides as the activities contributed an insignificant amount to the annual human dose.     

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.