Xinchi Hou

Theoretical modeling of yields for proton-induced reactions on natural and enriched molybdenum targets

Recent acute shortage of medical radioisotopes prompted investigations into alternative methods of production and the use of a cyclotron and ¹⁰⁰Mo(p,2n)(99m)Tc reaction has been considered. In this context, the production yields of (99m)Tc and various other radioactive and stable isotopes which will be created in the process have to be investigated, as these may affect the diagnostic outcome and radiation dosimetry in human studies. Reaction conditions (beam and target characteristics, and irradiation and cooling times) need to be optimized in order to maximize the amount of (99m)Tc and minimize impurities. Although ultimately careful experimental verification of these conditions must be performed, theoretical calculations can provide the initial guidance allowing for extensive investigations at little cost. We report the results of theoretically determined reaction yields for (99m)Tc and other radioactive isotopes created when natural and enriched molybdenum targets are irradiated by protons. The cross-section calculations were performed using a computer program EMPIRE for the proton energy range 6-30 MeV. A computer graphical user interface for automatic calculation of production yields taking into account various reaction channels leading to the same final product has been created. The proposed approach allows us to theoretically estimate the amount of (99m)Tc and its ratio relative to (99g)Tc and other radioisotopes which must be considered reaction contaminants, potentially contributing to additional patient dose in diagnostic studies.

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.

44gSc production using a water target on a 13 MeV cyclotron

INTRODUCTION Access to promising radiometals as isotopes for novel molecular imaging agents requires that they are routinely available and inexpensive to obtain. Proximity to a cyclotron center outfitted with solid target hardware, or to an isotope generator for the metal of interest is necessary, both of which can introduce significant hurdles in development of less common isotopes. Herein, we describe the production of ⁴⁴Sc (t1/2=3.97 h, Eavg,β⁺=1.47MeV, branching ratio=94.27%) in a solution target and an automated loading system which allows a quick turn-around between different radiometallic isotopes and therefore greatly improves their availability for tracer development. Experimental yields are compared to theoretical calculations. METHODS Solutions containing a high concentration (1.44-1.55g/mL) of natural-abundance calcium nitrate tetrahydrate (Ca(NO₃)2·4 H₂O) were irradiated on a 13MeV proton-beam cyclotron using a standard liquid target. (44g)Sc was produced via the ⁴⁴Ca(p,n)(44g)Sc reaction. RESULTS (44g)Sc was produced for the first time in a solution target with yields sufficient for early radiochemical studies. Saturation yields of up to 4.6 ± 0.3 MBq/μA were achieved using 7.6 ± 0.3 μA proton beams for 60.0 ± 0.2 minutes (number of runs n=3). Experimental data and calculation results are in fair agreement. Scandium was isolated from the target mixture via solid-phase extraction with 88 ± 6% (n=5) efficiency and successfully used for radiolabelling experiments. The demonstration of the production of ⁴⁴Sc in a liquid target greatly improves its availability for tracer development.

Theoretical dosimetry estimations for radioisotopes produced by proton-induced reactions on natural and enriched molybdenum targets

This study presents a summary of the dosimetry calculations performed for three technetium agents most commonly used in nuclear medicine diagnostic studies, namely sestamibi™, phosphonates and pertechnetate, labeled with cyclotron-produced technetium. Calculated patient doses were compared to those that would be delivered by the same radiotracers labeled with technetium obtained from a generator produced in a reactor. The main difference is that technetium from a generator is pure, i.e. contains only (99m)Tc and its decay product (99g)Tc, while in a cyclotron a large number of other stable and radioactive isotopes are created. In our calculations only technetium radioisotopes (ground and isomeric states) were considered as they will be included in the radiotracer labeling process and will contribute to the patient dose. Other elements should be removed by chemical purification. These dose estimates are based on our theoretical calculations of the proton-induced reaction cross sections and radioisotope production yields. Thick targets of enriched (three different compositions) and natural molybdenum, and three initial beam energies (16, 19 and 24 MeV) were considered for irradiation times of 3, 6 and 12 h with a beam current of 200 µA. The doses were calculated for injection times corresponding to 0, 2, 8, 12 and 24 h after the end of beam.

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.

Production of Y-86 and other radiometals for research purposes using a solution target system.

INTRODUCTION Diagnostic radiometals are typically obtained from cyclotrons by irradiating solid targets or from radioisotope generators. These methods have the advantage of high production yields, but require additional solid target handling infrastructure that is not readily available to many cyclotron facilities. Herein, we provide an overview of our results regarding the production of various positron-emitting radiometals using a liquid target system installed on a 13 MeV cyclotron at TRIUMF. Details about the production, purification and quality control of (89)Zr, (68)Ga and for the first time (86)Y are discussed. METHODS Aqueous solutions containing 1.35-1.65 g/mL of natural-abundance zinc nitrate, yttrium nitrate, and strontium nitrate were irradiated on a 13 MeV cyclotron using a standard liquid target. Different target body and foil materials were investigated for corrosion. Production yields were calculated using theoretical cross-sections from the EMPIRE code and compared with experimental results. The radioisotopes were extracted from irradiated target material using solid phase extraction methods adapted from previously reported methods, and used for radiolabelling experiments. RESULTS We demonstrated production quantities that are sufficient for chemical and biological studies for three separate radiometals, (89)Zr (Asat = 360 MBq/μA and yield = 3.17 MBq/μA), (86)Y (Asat = 31 MBq/μA and yield = 1.44 MBq/μA), and (68)Ga (Asat = 141 MBq/μA and yield = 64 MBq/μA) from one hour long irradiations on a typical medical cyclotron. (68)Ga yields were sufficient for potential clinical applications. In order to avoid corrosion of the target body and target foil, nitrate solutions were chosen as well as niobium as target-body material. An automatic loading system enabled up to three production runs per day. The separation efficiency ranged from 82 to 99%. Subsequently, (68)Ga and (86)Y were successfully used to radiolabel DOTA-based chelators while deferoxamine was used to coordinate (89)Zr.

Molybdenum target specifications for cyclotron production of 99mTc based on patient dose estimates

In response to the recognized fragility of reactor-produced (99)Mo supply, direct production of (99m)Tc via (100)Mo(p,2n)(99m)Tc reaction using medical cyclotrons has been investigated. However, due to the existence of other Molybdenum (Mo) isotopes in the target, in parallel with (99m)Tc, other technetium (Tc) radioactive isotopes (impurities) will be produced. They will be incorporated into the labeled radiopharmaceuticals and result in increased patient dose. The isotopic composition of the target and beam energy are main factors that determine production of impurities, thus also dose increases. Therefore, they both must be considered when selecting targets for clinical (99m)Tc production. Although for any given Mo target, the patient dose can be predicted based on complicated calculations of production yields for each Tc radioisotope, it would be very difficult to reverse these calculations to specify target composition based on dosimetry considerations. In this article, a relationship between patient dosimetry and Mo target composition is studied. A simple and easy algorithm for dose estimation, based solely on the knowledge of target composition and beam energy, is described. Using this algorithm, the patient dose increase due to every Mo isotope that could be present in the target is estimated. Most importantly, a technique to determine Mo target composition thresholds that would meet any given dosimetry requirement is proposed.

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.

Quantitative analysis of relationships between irradiation parameters and the reproducibility of cyclotron-produced 99mTc yields

Cyclotron production of (99m)Tc through the (100)Mo(p,2n) (99m)Tc reaction channel is actively being investigated as an alternative to reactor-based (99)Mo generation by nuclear fission of (235)U. An exciting aspect of this approach is that it can be implemented using currently-existing cyclotron infrastructure to supplement, or potentially replace, conventional (99m)Tc production methods that are based on aging and increasingly unreliable nuclear reactors. Successful implementation will require consistent production of large quantities of high-radionuclidic-purity (99m)Tc. However, variations in proton beam currents and the thickness and isotopic composition of enriched (100)Mo targets, in addition to other irradiation parameters, may degrade reproducibility of both radionuclidic purity and absolute (99m)Tc yields. The purpose of this article is to present a method for quantifying relationships between random variations in production parameters, including (100)Mo target thicknesses and proton beam currents, and reproducibility of absolute (99m)Tc yields (defined as the end of bombardment (EOB) (99m)Tc activity). Using the concepts of linear error propagation and the theory of stochastic point processes, we derive a mathematical expression that quantifies the influence of variations in various irradiation parameters on yield reproducibility, quantified in terms of the coefficient of variation of the EOB (99m)Tc activity. The utility of the developed formalism is demonstrated with an example. We show that achieving less than 20% variability in (99m)Tc yields will require highly-reproducible target thicknesses and proton currents. These results are related to the service rate which is defined as the percentage of (99m)Tc production runs that meet the minimum daily requirement of one (or many) nuclear medicine departments. For example, we show that achieving service rates of 84.0%, 97.5% and 99.9% with 20% variations in target thicknesses requires producing on average 1.2, 1.5 and 1.9 times the minimum daily activity requirement. The irradiation parameters that would be required to achieve these service rates are described. We believe the developed formalism will aid in the development of quality-control criteria required to ensure consistent supply of large quantities of high-radionuclidic-purity cyclotron-produced (99m)Tc.