Milan Vuckovic

Implementation of Multi-Curie Production of 99mTc by Conventional Medical Cyclotrons

99mTc is currently produced by an aging fleet of nuclear reactors, which require enriched uranium and generate nuclear waste. We report the development of a comprehensive solution to produce 99mTc in sufficient quantities to supply a large urban area using a single medical cyclotron. Methods: A new target system was designed for 99mTc production. Target plates made of tantalum were coated with a layer of 100Mo by electrophoretic deposition followed by high-temperature sintering. The targets were irradiated with 18-MeV protons for up to 6 h, using a medical cyclotron. The targets were automatically retrieved and dissolved in 30% H2O2. 99mTc was purified by solid-phase extraction or biphasic exchange chromatography. Results: Between 1.04 and 1.5 g of 100Mo were deposited on the tantalum plates. After high-temperature sintering, the 100Mo formed a hard, adherent layer that bonded well with the backing surface. The targets were irradiated for 1–6.9 h at 20–240 μA of proton beam current, producing up to 348 GBq (9.4 Ci) of 99mTc. The resulting pertechnetate passed all standard quality control procedures and could be used to reconstitute typical anionic, cationic, and neutral technetium radiopharmaceutical kits. Conclusion: The direct production of 99mTc via proton bombardment of 100Mo can be practically achieved in high yields using conventional medical cyclotrons. With some modifications of existing cyclotron infrastructure, this approach can be used to implement a decentralized medical isotope production model. This method eliminates the need for enriched uranium and the radioactive waste associated with the processing of uranium targets.

Cross-Linked Polyethylene Glycol Beads to Separate 99mTc-Pertechnetate from Low-Specific-Activity Molybdenum

We report a kit-based approach for the purification of sodium pertechnetate (99mTcO4−) from solutions with high MoO42− content. Methods: Cross-linked polyethylene glycol resins (ChemMatrix) were used to separate 99mTc and molybdenum in 4N NaOH. The resins were loaded at various flow rates and eluted with water to release 99mTc. The 99mTc solution was passed through a cation exchange resin and an alumina cartridge, followed by saline elution. This process was tested with cyclotron-produced 99mTc using an automated system and disposable kits. Results: Optimal results were obtained by loading 500 mg of resin at flow rates of up to 3.1 mL/min, with quantitative extraction of 99mTc from the molybdate solution and complete release of 99mTc after elution with water. The automated system was highly efficient at isolating Na99mTcO4 within minutes, with a recovery rate of 92.7% ± 1.1% (mean ± SD) using cyclotron-produced 99mTc. Conclusion: ChemMatrix resins were highly effective at separating 99mTcO4− from molybdate solutions.

Graphical user interface for yield and dose estimations for cyclotron-produced technetium

The cyclotron-based (100)Mo(p,2n)(99m)Tc reaction has been proposed as an alternative method for solving the shortage of (99m)Tc. With this production method, however, even if highly enriched molybdenum is used, various radioactive and stable isotopes will be produced simultaneously with (99m)Tc. In order to optimize reaction parameters and estimate potential patient doses from radiotracers labeled with cyclotron produced (99m)Tc, the yields for all reaction products must be estimated. Such calculations, however, are extremely complex and time consuming. Therefore, the objective of this study was to design a graphical user interface (GUI) that would automate these calculations, facilitate analysis of the experimental data, and predict dosimetry. The resulting GUI, named Cyclotron production Yields and Dosimetry (CYD), is based on Matlab®. It has three parts providing (a) reaction yield calculations, (b) predictions of gamma emissions and (c) dosimetry estimations. The paper presents the outline of the GUI, lists the parameters that must be provided by the user, discusses the details of calculations and provides examples of the results. Our initial experience shows that the proposed GUI allows the user to very efficiently calculate the yields of reaction products and analyze gamma spectroscopy data. However, it is expected that the main advantage of this GUI will be at the later clinical stage when entering reaction parameters will allow the user to predict production yields and estimate radiation doses to patients for each particular cyclotron run.

A fast and simple dose-calibrator-based quality control test for the radionuclidic purity of cyclotron-produced (99m)Tc.

Cyclotron production of 99mTc through the (100)Mo(p,2n)99mTc reaction channel is actively being investigated as an alternative to reactor-based (99)Mo generation by nuclear fission of (235)U. Like most radioisotope production methods, cyclotron production of 99mTc will result in creation of unwanted impurities, including Tc and non-Tc isotopes. It is important to measure the amounts of these impurities for release of cyclotron-produced 99mTc (CPTc) for clinical use. Detection of radioactive impurities will rely on measurements of their gamma (γ) emissions. Gamma spectroscopy is not suitable for this purpose because the overwhelming presence of 99mTc and the count-rate limitations of γ spectroscopy systems preclude fast and accurate measurement of small amounts of impurities. In this article we describe a simple and fast method for measuring γ emission rates from radioactive impurities in CPTc. The proposed method is similar to that used to identify (99)Mo breakthrough in generator-produced 99mTc: one dose calibrator (DC) reading of a CPTc source placed in a lead shield is followed by a second reading of the same source in air. Our experimental and theoretical analysis show that the ratio of DC readings in lead to those in air are linearly related to γ emission rates from impurities per MBq of 99mTc over a large range of clinically-relevant production conditions. We show that estimates of the γ emission rates from Tc impurities per MBq of 99mTc can be used to estimate increases in radiation dose (relative to pure 99mTc) to patients injected with CPTc-based radiopharmaceuticals. This enables establishing dosimetry-based clinical-release criteria that can be tested using commercially-available dose calibrators. We show that our approach is highly sensitive to the presence of 93gTc, 93mTc, 94gTc, 94mTc, 95mTc, 95gTc, and 96gTc, in addition to a number of non-Tc impurities.

Accuracy, reproducibility, and uncertainty analysis of thyroid-probe-based activity measurements for determination of dose calibrator settings

PURPOSE In the nuclear medicine department, the activity of radiopharmaceuticals is measured using dose calibrators (DCs) prior to patient injection. The DC consists of an ionization chamber that measures current generated by ionizing radiation (emitted from the radiotracer). In order to obtain an activity reading, the current is converted into units of activity by applying an appropriate calibration factor (also referred to as DC dial setting). Accurate determination of DC dial settings is crucial to ensure that patients receive the appropriate dose in diagnostic scans or radionuclide therapies. The goals of this study were (1) to describe a practical method to experimentally determine dose calibrator settings using a thyroid-probe (TP) and (2) to investigate the accuracy, reproducibility, and uncertainties of the method. As an illustration, the TP method was applied to determine 188Re dial settings for two dose calibrator models: Atomlab 100plus and Capintec CRC-55tR. METHODS Using the TP to determine dose calibrator settings involved three measurements. First, the energy-dependent efficiency of the TP was determined from energy spectra measurements of two calibration sources (152Eu and 22Na). Second, the gamma emissions from the investigated isotope (188Re) were measured using the TP and its activity was determined using γ-ray spectroscopy methods. Ambient background, scatter, and source-geometry corrections were applied during the efficiency and activity determination steps. Third, the TP-based 188Re activity was used to determine the dose calibrator settings following the calibration curve method [B. E. Zimmerman et al., J. Nucl. Med. 40, 1508-1516 (1999)]. The interobserver reproducibility of TP measurements was determined by the coefficient of variation (COV) and uncertainties associated to each step of the measuring process were estimated. The accuracy of activity measurements using the proposed method was evaluated by comparing the TP activity estimates of 99mTc, 188Re, 131I, and 57Co samples to high purity Ge (HPGe) γ-ray spectroscopy measurements. RESULTS The experimental 188Re dial settings determined with the TP were 76.5 ± 4.8 and 646 ± 43 for Atomlab 100plus and Capintec CRC-55tR, respectively. In the case of Atomlab 100plus, the TP-based dial settings improved the accuracy of 188Re activity measurements (confirmed by HPGe measurements) as compared to manufacturer-recommended settings. For Capintec CRC-55tR, the TP-based settings were in agreement with previous results [B. E. Zimmerman et al., J. Nucl. Med. 40, 1508-1516 (1999)] which demonstrated that manufacturer-recommended settings overestimate 188Re activity by more than 20%. The largest source of uncertainty in the experimentally determined dial settings was due to the application of a geometry correction factor, followed by the uncertainty of the scatter-corrected photopeak counts and the uncertainty of the TP efficiency calibration experiment. When using the most intense photopeak of the samples emissions, the TP method yielded accurate (within 5% errors) and reproducible (COV = 2%) measurements of samples activity. The relative uncertainties associated with such measurements ranged from 6% to 8% (expanded uncertainty at 95% confidence interval, k = 2). CONCLUSIONS Accurate determination/verification of dose calibrator dial settings can be performed using a thyroid-probe in the nuclear medicine department.

Imaging study of using radiopharmaceuticals labeled with cyclotron-produced 99mTc

Cyclotron-produced 99mTc (CPTc) has been recognized as an attractive and practical substitution of reactor/generator based 99mTc. However, the small amount of 92-98Mo in the irradiation of enriched 100Mo could lead to the production of other radioactive technetium isotopes (Tc-impurities) which cannot be chemically separated. Thus, these impurities could contribute to patient dose and affect image quality. The potential radiation dose caused by these Tc-impurities produced using different targets, irradiation conditions, and corresponding to different injection times have been investigated, leading us to create dose-based limits of these parameters for producing clinically acceptable CPTc. However, image quality has been not considered. The aim of the present work is to provide a comprehensive and quantitative analysis of image quality for CPTc. The impact of Tc-impurities in CPTc on image resolution, background noise, and contrast is investigated by performing both Monte-Carlo simulations and phantom experiments. Various targets, irradiation, and acquisition conditions are employed for investigating the image-based limits of CPTc production parameters. Additionally, the relationship between patient dose and image quality of CPTc samples is studied. Only those samples which meet both dose- and image-based limits should be accepted in future clinical studies.

Radionuclidic purity measurements for cyclotron-produced 99mTc via 100Mo(p,2n) at 18 MeV

The radionuclidic purity of cyclotron-produced 99mTc has been measured by gamma ray spectroscopy and compared to the results of a quick release test modeled after the molybdenum breakthrough test performed on generator-derived 99mTc. Excellent radionuclidic purity is reported for samples produced at BCCA during our clinical trial. The quick release test results agree well with the gamma ray analysis.