Qucosa – Hemholtz-Zentrum Dresden-Rossendorf
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Proceedings of the 15th International Workshop on Targetry and Target Chemistry
Full text linkThe workshop is organized by the Nuclear Physics Institute of Academy of Sciences of the Czech Republic, public research institution, together with the Institute of Radiopharmaceutical Cancer Research of Helmholtz-Center Dresden-Rossendorf and in cooperation with the International Atomic Energy Agency (IAEA) and the support of many private sponsors. It is rather symbolic that Czech and German research institutions joined now freely their powers in order to organize this event
Challenges associated with thick target preparation of WO3 for high current production of 186Re via deuteron irradiation
Full text linkIntroduction
Rhenium-186 (t1/2 = 3.72 d) is very attractive for use as a theranostic agent in targeted radionuclide therapy (Eβ max = 1.072 MeV (> 76.6 %); Eγ = 137.2 keV)1. Previously published investigations of high specific activity 186Re production have utilized the 186W(p,n)186Re or 186W(d,2n)186Re reactions2-5. Our group is interested in the refinement and scale-up of the production of high specific activity 186Re by cyclotron irradiations of 186W with deuterons; including investigations of the most suitable target material. WO3 has been successfully used as a target material in proton irradiations by two other groups4,5. Further, the physical properties of WO3, such as the reported monoclinic with Pc space group, body centered cubic crystal structure6 and melting point of 1473 °C, made for an attractive target material as sintered and other more structurally robust pressed pellet target preparations could be explored. Thus, this study reports on the characterization and suitability of WO3 as a full-thickness target material for the deuteron production of 186Re.
Materials and Methods
Assessments of WO3 for target material suitability and structural integrity were made on thick targets (~1 g) prepared using both commercially available and converted WO3 by either uniaxially pressing (13.8 MPa) of powdered WO3 into an aluminum target support or by placing sintered WO3 pellets (1105 °C for 12 hours) into an aluminum target support.
In some experiments, WO3 pellets were prepared by dissolution of Wmetal with H2O2, then treatment with 1.5 M HCl. The recovered hydrated WO3 was calcinated at 800 °C for 4 hours, allowed to cool to ambient temperature, pulverized with a mortar and pestle, uniaxially pressed at 13.8 MPa into pellets with a 13 mm die, and subsequently sintered in a tube furnace under flowing Ar at 1105 °C for 3, 6, and 12 hours. Material characterization and product composition analyses were conducted with SEM, EDS, XRD, Raman spectroscopy, and visible photoluminescence spectroscopy.
Thick WO3 targets were irradiated for 10 min at 10 µA with nominal extracted deuteron energies of 17 MeV. Gamma-ray spectroscopy was per-formed to assess production yields and radionuclidic byproducts at least 24 hours post EOB.
Results
While the color of the commercially available WO3 is slightly different (dull, pale green) than the brighter more yellow color of the chemically processed WO3, X-ray diffraction spectrometry (XRD) indicated the two samples were virtually identical.
Attempts to determine how the duration of the sintering process (at 1105 °C) affects the chemical/physical nature of the pellet yielded surprising results. In contrast to the characteristic annealed appearance of sintered material, grains of the WO3 sample appeared more densely packed, but not sintered to one another as had been seen during higher temperature (1550 °C) reductions of WO3 irrespective of the time interval used.
Full-thickness pressed or sintered pellets of WO3 were found to disintegrate upon irradiation with the deuteron beam, allowing for the direct irradiation of the aluminum target body producing 24Na as a contaminant. Upon retrieval of the target support it was observed that the WO3 had vaporized, discoloring the surface of the well in the target support and coating the walls of ~61 cm (24 inches) of the terminal portion of the beamline, which then required decontamination. We believe that these observations are the result of outgassing oxygen species that subsequently reacted with the aluminum target support. While these findings are in sharp contrast with the successful production yields and isolations previously reported by both Shigeta et al. and Fassbender et al., we believe that these differences are attributable to differences in target design (previous studies utilized an en-closed target with cooling in front of and behind the target) necessitated by the configuration of our target station.
Conclusions.
The physical properties of powdered WO3, including its lower melting point and more suitable compressibility than powdered Wmetal, seemed to enhance the structural integrity of a WO3 pellet (whether pressed or sintered). However, when compared to our recent successes with the use of Wmetal based targets, the disappointing degradation of our WO3 targets when irradiated with the incident deuteron beam has led us to believe that Wmetal is the more viable target material for 186Re production in our facility
Molybdenum targets for production of 99mTc by a medical cyclotron
Full text linkIntroduction
Alternative methods for producing the medical imaging isotope 99mTc are actively being developed around the world in anticipation of the imminent shutdown of the National Research Universal (NRU) reactor in Chalk River, Ontario, Canada and the high flux reactor (HFR) in Petten, Holland that together currently produce up to 80 % of the world’s supply through fission. The most promising alternative methods involve accelerators that focus Bremsstrahlung radiation or protons on metallic targets comprised of 100Mo and a supporting material used to conduct heat away during irradiation. As an example, the reaction 100Mo(p,2n)99mTc provides a direct route that can be incorporated into routine production in regional nuclear medicine centers that possess medical cyclotrons for production of other isotopes, such as those used for Positron Emission Tomography (PET).
The targets used to produce 99mTc are subject to a number of operational constraints. They must withstand the temperatures generated by the irradiation and be fashioned to accommodate temperature gradients from in situ cooling. The targets must be resilient, which means they cannot disintegrate during irradiation or post processing, because of the radioactive nature of the products. Yet, the targets must be easily post-processed to separate the 99mTc. In addition, the method used to manufacture the targets must not be wasteful of the 100Mo, because of its cost (~$2/mg). Any manufacturing process should be able to function remotely in a shielded space to accommodate the possibility of radioactive recycled target feedstock. There are a number of methods that have been proposed for large-scale target manufacturing including electrophoretic deposition, pressing and sinter-ing, electroplating and carburization [1]. How to develop these methods for routine production is an active business [2,3]. From the industrial perspective, plasma spraying showed promising results initially [4], but the process became very expensive requiring customized equipment in order to reduce losses because of overspray,which also required a large inventory of expen-sive feedstock. In this paper we report the ex-perimental validation of an industrial process for production of targets comprising a Mo layer and a copper support.
Materials and methods
Target Design
Targets have been manufactured for irradiation at 15 MeV. Two targets are shown in FIG. 1: one as-manufactured and another after irradiation; no visible changes were observed following irradiation. The supporting circular copper (C101) disks have diameters of 24 mm and thickness of 1.6 mm. The molybdenum in the center of the target is fully dense with thickness 230 μm determined from SEM cross-sections.Targets have also been manufactured for irradi-ation in a general-purpose target holder designed to be attached to all makes of cyclotrons found in regional nuclear medicine centers. The elliptical targets were designed for high-volume production of 99mTc with 15 MeV protons at currents of 400 µA with 15% collimation [4]. The elliptical shape reduces the heat flux associated with high current sources. The cooling channels on the back of the target are designed to with-stand the high temperature generated during Irradiation.
A thermal simulation of expected temperatures during irradiation is shown in FIG. 3. The center of the target is expected to reach 260 oC during irradiation. The elliptical targets were formed from a 27 mm C101 copper plate with width 22 mm and length 55 mm. The molybdenum in the center of the target is fully dense with thickness 60 m de-termined from SEM cross-sections. FIG. 4 shows the molybdenum deposition in the center of the target in a form of an ellipse (38×10 mm).
Results and Conclusions
Circular targets have been produced and suc-cessfully irradiated for up to 5 h with a proton beam with energy 15 MeV and current 50 µA. (FIG. 1). The targets were resilient. Before irradi-ation the targets were subjected to mechanical shock tests and thermal gradients with no ob-servable effect. After irradiation there was no indication of any degradation. The manufacturing process produced 20 consistently reproducible targets within an hour with a molybdenum loss of less than 2 %. After irradiation the targets were chemically processed and the products characterized by Ge-HP gamma spectrometry. Only Tc isotopes were found. No other contami-nants were identified after processing. The de-tails of the separation and purification are de-scribed elsewhere [5].
Circular targets suitable for low-volume produc-tion of 99mTc have been manufactured and test-ed. The targets have been shown to meet the required operation constraints: the targets are resilient withstanding mechanical shock and irradiation conditions; they are readily produced with minimal losses; and post-processing after irradiation for 5 h has been shown to produce 99mTc.
Elliptical targets suitable for high-volume pro-duction of 99mTc with high power cyclotrons have been manufactured (FIG. 4). Like the circular targets, the elliptical targets are readily pro-duced with minimal losses and are able to with-stand mechanical shock and thermal gradients; however, they have yet to be irradiated
Isotope harvesting at heavy ion fragmentation facilities
Full text linkIntroduction
The National Superconducting Cyclotron Laboratory (NSCL) is a national nuclear physics facility in which heavy ion beams are fragmented to produce exotic nuclei. In this process of fragmentation many nuclei are created, however, only one isotope is selected for experimentation. The remaining isotopes that are created go unused. The future upgrade of the NSCL to the Facility for Rare Isotope Beams (FRIB) will increase the incident energy of these heavy ion beams and amplify the current by three orders of magnitude. An aqueous beam dump will be created to collect the unused isotopes created in the process of fragmentation. Several of these isotopes are of interest for many applications including nuclear security, medical imaging, and therapy and are not currently available or are only available in very limited supply. Harvesting these isotopes from the aqueous beam dump could provide a consistent supply of these im-portant isotopes as an ancillary service to the existing experimental program.
Material and Methods
A liquid water target system was designed and tested to serve as a mock beam dump for exper-iments at the NSCL1. A 25 pnA 130 MeV/u 76Ge beam was fragmented using a 493 mg/cm2 thick beryllium production target. After fragmentation the beam was separated using the A1900 frag-ment separator2 set up for maximum 67Cu pro-duction using a 240 mg/cm2 aluminum wedge and a 2% momentum acceptance. The secondary beam was collected for four hours in the liquid water target system before being transferred to a collection vessel. Four additional four hour collections were made before finally shipping the five collections to Washington University and Hope College for chemical separation.
Four of the five samples were separated using a two part separation scheme. First they were passed through and 3M Empore iminodiacetic acid functionalized chelation disk in a 1.25M ammonium acetate solution at pH 5. The flow through was collected and analyzed using an HPGe detector. Then 10mL of 6M HCl acid was passed through the chelation disk to remove the 2+ transition metals. The 10mL of 6M HCl acid was collected after passing through the disk and added to an anion-exchange column with 2.5 g AG1-X8 resin. The eluate was collected and then an additional 10mL of 6M HCl was passed through the column to remove the nickel. The 67Cu was then collected by passing 10mL of 0.5M HCl and the eluate was collected in 1mL fractions each analyzed by HPGe for 67Cu concentration and purity. The two highest 67Cu fractions were heated to dryness and reconstituted in 50 μL 0.1M ammonium acetate pH 5.5.
2 μL of 7.9 mg/mL NOTA-Bz-Trastuzumab was added to 45 μL of 67Cu and 3 μL 0.1M ammonium acetate pH 5.5. This solution was placed in a shaking incubator at 37 °C for twenty minutes and then analyzed by radio-instant thin layer chromatography in order to determine the per-cent of 67Cu bound to the antibody.
Results and Conclusion
67Cu was collected into the liquid water target system with an average efficiency of 85 ± 5 %. The secondary beam was 73 % pure with the impurities, half-lives greater than 1 minute, listed in TABLE 1.
Separation of 67Cu from the impurities resulted in an average recovery of 88 ± 3 % for a total recovery of 67Cu from the beam and separation of 75 ± 4 %. No detectable radioactive impurities were found in the final samples when analyzed using an HPGe detector. TABLE 2 shows the amount of 67Cu collected from the beam and the amount recovered decay corrected to end of bombardment. Labeling NOTA-Bz-Trastuzumab with 67Cu resulted in > 95 % radiochemical yield.
Collection of the 73 % pure 67Cu beam in water and the resulting separation proved successful. These results demonstrate that radioisotopes can be collected from fragmented heavy ion beams and isolated in usable quantities and purity for many radiochemical applications. Further experimentation with an unpurified beam to better simulate conditions in the beam dump at the Facility for Rare Isotope Beams will be performed in the near future
Cross section measurements on 61Cu for proton beam monitoring above 20 MeV
Full text linkIntroduction
All experimental studies involving charged particle induced nuclear reactions require a precise knowledge of monitor reactions. A number of well described proton induced monitor reactions exist in the lower energy range [1], which is covered by most medical cyclotrons. Concerning proton energies above 20 MeV, however, the accuracy of the monitor reactions declines as cross section data becomes scarcer. Furthermore, the growing interest in precise determination of projectile energies by comparing of ratios of monitor reaction cross sections demands new measurements and evaluations of known data for high threshold monitor radionuclides.
In this work cross section measurements on the formation of 61Cu were done and energy de-pendent radionuclide ratios were calculated.
Material and Methods
For investigation of the natCu(p,x)61Cu reaction copper foils of natural isotopic composition (Goodfellow Ltd.) were irradiated. The targets were of 10 and 20 μm thickness, having a diameter of 15 mm.
Proton bombardments up to 45 MeV incident energy were done in the stacked-foil arrangement at the accelerator JULIC of the Nuclear Physics Institute (IKP) of the Forschungszentrum Jülich. In addition to an internal irradiation possibility the cyclotron is equipped with an external target station which was used for most experiments. It can adapt standard and slanting solid target holders and is equipped with a water cooled four sector collimator and additional helium cooling of the entry foil.
Several irradiations were executed. In each stack, besides copper samples, aluminium absorbers and additional nickel monitor foils were also placed, the latter for the determination of the respective beam current.
The produced radioactivity of 61Cu was analysed non-destructively using HPGe γ-ray detectors (EG&G Ortec).
Results and Conclusion
Reaction cross sections of the natCu(p,x)61Cu process up to 45 MeV were measured and com-pared with existing data from the literature (FIG. 2). Except for the data of Williams et al. our results are in good agreement, showing a maxi-mum of about 165 mbarn at 37.5 MeV proton energy. The overall uncertainty of the new cross section data is between 8 and 10 %.
In FIG. 3, the excitation functions of the relevant monitor reactions on Cu are shown.
In combination with the excitation function of the natCu(p,xn)62Zn reaction, isotope ratios were calculated which can be used for determination of the proton energy within a target stack in the energy range of 22–40 MeV as described by Piel et al. [3]. FIGURE 4 shows the cross section ratio in dependence of the proton energy.
Above this energy, 65Zn could be used to generate isotope ratios for energy determination, although the long half-life (T½ = 244.3 d) of that radionuclide may be a problem.
Additional cross section measurements are planned in order to further strengthen the data base of this potential monitor reaction. The results of this work shall be evaluated in the framework of an ongoing Coordinated Research Project of the IAEA
Further exploration of C-11 HP target on PETtrace
Full text linkIntroduction
At WTTC 14 we presented data on the target yields of our GE PETtrace C-11 HP target in comparison to the target yields we had been getting on the MC17 prior to its decommissioning1. Discussion with other attendees alerted us to the fact that the target may be too “thin”, allowing the beam to spread out and interact with the walls, which could result in a lower target yield. Additionally, a GE service engineer indicated that we could be striking the top of the target with some of the beam, due both to target thinning and the “banana” effect from the magnetic fringe fields. Experiments were carried out to determine the potential magnitude of this effect and the efficacy of potential solutions.
Material and Methods
All experiments were performed on a GE PET-trace cyclotron. The first set of experiments was performed on the C-11 HP target in its natural mounting state (no aids). The change is gas pressure as a function of beam current was measured, from 5 to 70 microamps for three different gas fill pressures: 210, 230 and 250 PSI. The second set of experiments was performed after mechanically lifting the back end of the target with a box, changing the target angle from 23.9 degrees past horizontal to 25.2 degrees past horizontal. While this change in angle does not seem drastic, it did pick up all the slack in the target mount due the sagging of the target from its longer length than other GE targets. The change in gas pressure as a function of beam current was measured, from 5 to 80 microamps for four different gas fill pressures: 190, 210, 230 and 250 PSI. (Note that the box is a temporary solution and the target will sag over time without a more permanent solution for supporting the back end of the target.)
Results and Conclusion
The graphical results of pressure rise as a function of beam current are shown in FIGURE 1. Note that measurements were stopped when the pressure approached 470 PSI, based on advice from GE engineers. There is some flattening out for the 190-PSI data, even with the increase in angle as an attempt to counteract the banana effect (note that GE’s recommended fill pressure is 187 PSI). Increases in the fill pressure helped in keeping the target thick, but with the tradeoff that less beam can be put onto the target before reaching the maximum specified pressure. Final-ly, using a lifting mechanism to raise the back of the target also helped to prevent thinning, as seen in the r-squared values for the linear fit, shown in TABLE 1. The data presented indicate that a shorter target that can withstand higher pressures could be beneficial for the PETtrace cyclotron, allowing the beam to fully stop before striking the walls, be it through target thinning or the “banana” effect while still allowing the user to run high beam currents
Monte-Carlo simulation with FLUKA for liquid and solid targets
Full text linkIntroduction
Monte-Carlo simulations can be used to assess isotope production on small medical cyclotrons. These simulations calculate the particle interactions with electric and magnetic fields, as well as the nuclear reactions. The results can be used to predict both yields and isotopic contaminations and can aid in the optimum design of target material and target geometry [1,2]. FLUKA is a general-purpose tool widely used in many applications from accelerator shielding to target design, calorimetry, activation, dosimetry, detector design, neutrino physics, or radiotherapy [3,4]. In this work, we applied the Monte-Carlo code FLUKA to determine the accuracy of predicting yields of various isotopes as compared to experimental yields.
Material and Methods
The proton beam collimation system, as well as the liquid and solid target of the TR13 cyclotron at TRIUMF, has been modeled in FLUKA. The proton beam parameters were initially taken from the cyclotron design specifications and were optimized against experimental measurements from the TR13. Data from irradiations of different targets and with different beam currents were collected in order to account for average behavior, see FIG. 1. Yields for a pencil proton beam as well as a beam spread out in direction and energy have been calculated and have been compared to experimental results obtained with the TR13.
Results and Conclusion
The reactions listed in TABLE 1 were assessed. For most reactions a good agreement was found in the comparison between experimental and simulated saturation yield. TABLE 1 only shows the yields simulated with a proton beam with a spread in both direction and energy. In most cases, the simulated yield is slightly larger or comparable. Only the calculated yield for 55Co was significantly lower by a factor of 4.2. This is still a good agreement considering that FLUKA was originally a high-energy physics code. It may indicate that the FLUKA internal cross-section calculation for this isotope production needs some optimization. In summary, we conclude that FLUKA can be used as a tool for the prediction of isotope production as well as for target design
Thermal separation of 99mTc from Molybdenum targets
Full text linkThermal separation is defined as a mass transfer process driven by molecular forces. The process involves the heat transfer between two phases with different composition. In general, thermal separation occurs when heat is generated in the system additionally to the already existing phases. In a second phase the mass is transferred in the system (adsorption) and at the end of this step the separation is completed. The thermal separation can be achieved in temperature or concentration gradient function of system configuration [1]. Thermo-chromatography is a process in which the separation occurs in gase-ous phase. By passing a heated gas through a column a thermal gradient is created with a continuously decreasing temperature along the column. The separation occurs based on the different volatilization temperatures, the less volatile species will condense on the column walls at the higher temperatures and the highly volatile compounds will condense at lower temperatures. Parameters like temperature, carrier flow rate, column geometry and length have impact on the absorption of the compound on the column material affecting the separation efficiency. The thermal separation has been used for separation of Molybdenum (Mo) and Technetium (Tc) by either sublimation in the case of 94mTc {2,3,4] or dry distillation in the case of 99mTc from neutron irradiated MoO3 [5]. The thermal separation process has been used in the development of a new type of Mo/Tc generators starting from the MoO3 as target material for production of 99mTc in linear accelerators [6]. Dry distillation has become a standard procedure for separation of radioiodine from tellurium targets [7]. The present paper describes the thermal separation of a three component system (Cu/Mo/Tc) used as a target in the production of 99mTc through the 100Mo(p,2n) reaction.
Material and Methods
The separation method involves the use of oxygen as a carrier gas and oxidation agent. The method is based on the different volatilization temperatures of Tc formed oxides and the MoO3 formed in the system during the oxidation. In the presence of oxygen the existing Tc is oxidized to its anhydride as Tc2O7 (b.p. 319 ⁰C; m.p. 110.9 ⁰C) following the reaction:
4Tc + 7O2 →2Tc2O7
The T2O7 has a saturated vapor pressure of 310 ⁰C whilst Mo is completely oxidized to MoO3 having a sublimation temperature at 750 ⁰C. The initial experimental setup comprised a quartz tube (6 mm internal diameter, 40 cm long) which is introduced into a horizontal tube furnace (model 55035A, Lindberg). The left end of the quartz tube is connected to a pure oxygen supply which flows through the separation tube at a rate of 10 mL/min. The other end of the tube is opened to the atmosphere and protected with quartz wool. The quartz tube is heated over a length of 23 cm at a temperature of 850 ⁰C. The heated carrier gas is flowing on the tube length and the temperature gradient is created along the tube from 850 ⁰C to room temperature. During the process, the oxygen carries out the Tc oxides to a lower temperature and Tc2O7 is deposited in the cooler region of the tube in a similar manner as described by Tachimory [5]. The temperature gradient is calibrated by meas-uring the temperature inside the tube at each centimeter along its length (FIG. 1).
The radioactivity counting is performed by scan-ning the tube along its length every 2 centimeters by using a detection system shown in figure 2. The system comprises a GM tube coupled to a computer controlled linear actuator (Velmex Unislide). The tube is placed at a distance of approximately 25 mm from the collimator of GM.
Preliminary testing using Mo powder
Prior to testing the three component separation, a reference test was performed by using 120 mg of natural Mo powder (Alpha Aesar, 99.9 %) soaked with 50 MBq NaTcO4 (Cardinal Health, radiochemical purity >95 %). After evaporation the dried powder was introduced into a quartz tube (6 mm ID, 40 mm long) and heated up to 850 ⁰C in the presence of oxygen flowing at a rate of 10 mL/min.
Three component separation
The targets prepared for the production of 99mTc by a cyclotron were comprised of copper (Cu) (C101, oxygen free) support having a Mo layer deposited on the surface in an elliptical form as described in literature [8,9]. About 60 to 250 mg of Mo (99.9%, Alpha Aesar) was deposited on the target surface. 70 MBq of Tc (Cardinal Health) as NaTcO4 (> 99 % radiochemical purity) was deposited on the Mo insert to mimic the conditions created during proton irradiation. The Tc spike was evaporated to dryness and the Cu/Mo/Tc target was then introduced into the experimental setup. The process was allowed to continue for 20 min. The experiment was carried out by inserting the target plates in a quartz tube (CanSci, Canada) of similar design to those described by Fonslet for the separation of radio-iodine from TeO2 targets [7]. The quartz tube can be seen in FIG. 2 and illustrated with dimensions indicated in FIG. 3.
Separation of in-situ cyclotron produced Tc by irradiation of Mo targets with a proton beam.
A third set of experiments have been performed for in-situ generated Tc by irradiation of circular targets containing approximately 60 mg Mo deposited on a copper support. The targets were irradiated for 30 min with a proton beam with the energy of 15 MeV and a current of 50 µA. The separation was performed using similar experimental conditions as previously described. The quartz tube was scanned in length by using a RadioTLC scanning system calibrated for 99mTc and 99Mo isotopes.
After the thermal separation was completed 99mTc was recovered as NaTcO4 by selectively washing the quartz tube with 1 M NaOH (Fisher) solution. The presence of Mo in the NaTcO4 solution was verified by a colorimetric strip test (EM-Quant Mo test kit, Millipore). The presence of copper was qualitatively analyzed by adding a few drops of concentrated NH4OH (Fisher) solution and checking the formation of Schweitzer reagent.
Results
Thermal separation of Tc-Mo powder
After 20 min the deposition of MoO3 was ob-served as yellow crystals in the region of tem-perature of 770 ⁰C, which is in accordance with the results reported in the literature [5]. The activity of 99mTc was detected at about 5 cm from the exit of the tube furnace in a temperature range starting with 310 ⁰C and ending at 46 ⁰C (FIG. 4)
New targetry possibilities from the TR-24
Full text linkIntroduction
The TR-24 is relatively new to the cyclotron market and its advantages over lower energy PET cyclotrons have not yet been fully realized. A new high current [18F] fluoride production target that takes advantage of the higher energy and current afforded by the TR-24 has been developed.
Material and Methods
The TR-24 cyclotron presents challenges of producing conventional PET isotopes even with its variable energy capability (18–25 MeV). Simultaneous irradiation of two targets that require different proton energies is possible only using beam energy degrader. Due to the relatively wide energy window, the degrader design is not trivial, especially for the high current operation. For example, reduction of beam energy from 24 to 18 MeV would require the use of an approximately 1.5 mm thick aluminum degrader. At 100 μA this degrader would have to be capable of dissipating 700 W of beam power, which would be challenging to achieve with no cooling or using a conventional helium cooling window. However, cooling water used as a beam energy degrader can dissipate several kilowatts of beam energy and provide additional cooling for target material and window foils. FIGURE 1 demonstrates the concept of the water cooled target window. A standard 18F- water target with a 2.5 mL fill volume and a 30 degree beam incident angle was modified to accept the new water window. A 1 mm thick region of circulating cooling water was inserted between the vacuum and the product foil.
The combined beam energy degradation caused by the vacuum foil (0.00012“ Havar), the cooling water (1 mm) and the target foil (0.00012“ Havar) was approximately 7 MeV for a 24 MeV incident proton energy.
The target was installed on a target selector mounted directly on the TR-24 cyclotron. No additional beam focusing or steering devices were used to defocus or correct beam shape. A small recirculation water system was setup to supply cooling water for the degrader. A mixed bed ion exchange column was installed on the return line to trap N-13 and radioactive metal ions that could possibly be etched from the Havar foils. The water in the degrader was continually circulated in a closed loop providing cooling to the vacuum and target foils. An 800mL/min water flow through the degrader was generated by a low pressure water pump.
Results
Several tests were performed with O-16 water to establish current – pressure curve and to determine “burn through” current (FIGURE 2).
Conclusion
Initial tests demonstrated that the new F-18 target with a 1 mm water degrader is capable of accepting power levels in excess of 3.6 kW, operating at 150 μA. More testing is under way, including testing with H218O to determine the F-18 production capacity of this target. We will look into adapting this concept to all ACSI PET targets, including the high current F-18 produc-tion target which can potentially reach an operational current of 200 μA
Production and isolation of 72As from proton irradiation of enriched 72GeO2 for the development of targeted PET/MRI agents
Full text linkIntroduction
Two current major research topics in nuclear medicine are in the development of long-lived positron-emitting nuclides for imaging tracers with long biological half-lives and in theranostics, imaging nuclides which have a chemically analogous therapy isotope. As shown in TABLE 1, the radioisotopes of arsenic (As) are well suited for both of these tasks with several imaging and therapy isotopes of a variety of biologically relevant half-lives accessible through the use of small medical cyclotrons. The five naturally abundant isotopes of germanium are both a boon and challenge for the medical nuclear chemist. They are beneficial in that they facilitate a wide array of producible radioarsenic isotopes. They are a challenge as monoisotopic radioarsenic production requires isotopically-enriched targets that are expensive and of limited availability. This makes it highly desirable that the germanium target material is reclaimed from arsenic isolation chemistry.
One major factor which has limited the development of radioarsenic has been difficulties in its incorporation into biologically relevant targeting vectors. Previous studies have labeled antibodies and polymers through covalent bonding of arsenite (As(III)) with the sulfydryl group1,2,3. Recent work in our group has shown the facile synthesis and utility of superparamagnetic iron oxide nanoparticle- (SPION-)bound radioarsenic as a dual modality positron emission tomography (PET)/magnetic resonance imaging (MRI) agent4.
Presently, we have built upon previous studies producing, isolating, and labeling untargeted SPION with radioarsenic4,5. We have incorp-rated the use of isotopically-enriched 72GeO2 for the production of radioisotopically pure 72As. The bulk of the 72GeO2 target material was re-claimed from the arsenic isolation chemical procedure for reuse in future irradiations. The 72As was used for ongoing development toward the synthesis of targeted, As-SPION-based, dual-modality PET/MRI agents.
Material and Methods
Targets of ~100 mg of isotopically-enriched 72GeO2 (96.6% 72Ge, 2.86% 73Ge, 0.35% 70Ge, 0.2% 74Ge, 0.01% 76Ge, Isoflex USA) were pressed into a niobium beam stop at 225 MPa, covered with a 25 µm HAVAR containment foil, attached to a water-cooling target port, and irradiated with 3 µA of 16.1 MeV protons for 2–3 hours using a GE PETtrace cyclotron. After irradiation, the target and beam stop were assembled into a PTFE dissolution apparatus, where the 72GeO2 target material was dissolved with the addition of 2 mL of 4 M NaOH and subsequent stirring. After dissolution was completed, the clear, colorless solution was transferred to a fritted glass column and the bulk 72GeO2 was reprecipitated by neutralizing the solution with the addition of 630 µL [HCl]conc, filtered, and rinsed with 1 mL [HCl]conc. To the combined 72As-containing filtrates, 100 µL 30% H2O2 was added to ensure that 72As was in the nonvolatile As(V) oxidation state. The ~3 mL solution was then evaporated at 115 ˚C while the vessel was purged with argon, followed by a second addition of 100 µL H2O2 after the volume was reduced to 1 mL. When the filtrate volume was ~0.3 mL, the vessel was removed from heat, allowed to cool with argon flow, and the arsenic reconstituted in 1 mL [HCl]conc and loaded onto a 1.5 mL bed volume Bio-Rad AG 1×8, 200–400 mesh anion exchange column preconditioned with 10 M HCl. The radioarsenic was eluted in 10 M HCl in the next ~10 mL, with 90% of the activity eluting in a 4 mL fraction. The column was then eluted with 5 mL 1 M HCl. The 72As-rich 10 M HCl fraction was reduced to As(III) with the addition of ~100 mg CuCl, and heating to 60 ˚C for 1 hour. The resulting AsCl3 was then extracted twice into 4 mL cyclohexane, which were combined and back extracted into 500 µL of water as As(OH)3.
This solution of 72As in H2O was then used directly to label SPION and for subsequent experiments conjugating 72As-SPION with TRC105, an angiogenesis-marking monoclonal antibody (MAb) targeting endoglin/CD105. Several methods were initially attempted involving directly conjugating the surface-modified SPION to the MAb through a polyethylene glycol (PEG) linker. More recent studies have investigated the radioarsenic labeling of SPION encapsulated in hollow mesoporous silica nanoparticles (SPION@HMSN) and its subsequent conjugation to TRC105.
Results and Conclusion
Irradiation of pressed, isotopically-enriched 72GeO2 resulted in a production yield for 72As of 17 ± 2 mCi/(µA·hr·g) and for 71As of 0.37 ± 0.04 mCi/(µA·hr·g), which are 64 % and 33 %, of those predicted from literature6, respectively. However, these production yields are in agreement with those scaled from observed production yields using analagous natGeO2 targets. The end-of-bombardment 72As radionuclidic purity can be improved by minimizing the 72Ge(p,2n)71As reaction by degrading the beam energy. A 125 µm Nb containment foil would degrade impinging protons to 14.1 MeV and is predicted to reduce 71As yield by a factor of three, while only reducing 72As yield by 1 %6, improving end-of-bombardment radionuclidic purity from 98 % to greater than 99 %.
Overall decay-corrected radiochemical yield of the 72As isolation procedure from 72GeO2 were 51 ± 2 % (n = 3) in agreement with those observed with natGeO2 57 ± 7 % (n = 14). The beam current was limited to 3 µA as higher cur-rents 4–5 µA exhibited inconsistent dissolution and reprecipitation steps, resulting in an overall yield of 44 ± 21 % (n = 6). Dissolution time also played an important role in overall yield with at least one hour necessary to minimize losses in these first two steps. The separation procedure effectively removed all radiochemical contaminants and resulted in 72As(OH)3 isolated in a small volume, pH~4.5 water solution. Over the course of minutes to hours after back extraction, rapid auto-oxidation to 72AsO4H3 was observed. The bulk 72GeO2 target material, which was reclaimed from the isolation procedure, is being collected for future use.
The synthesis of a targeted PET/MRI agent based on the functionalization of 72As-SPION has proved to be a difficult task. Experiments conjugating 72As-SPION to TRC105 through a PEG linker were unsuccessful, despite the investigation of a variety bioconjugation procedures. Current work is investigating the use of SPION@HMSN, which have a similar affinity for 72As as unencapsulated SPION. This new class of 72As-labeled SPION@HMSN has a hollow cavity for potential anti-cancer drug loading, as well as the mesoporous silica surface, which may facilitate the efficient conjugation of TRC105 using a well-developed bioconjugation technique.
In summary, radioarsenic holds potential in the field of diagnostic and therapeutic nuclear medicine. However, this potential remains locked behind challenges related to its production and useful in vivo targeting. The present work strives to address several of these challenges through the use of enriched 72GeO2 target material, a chemical isolation procedure that reclaims the bulk of the target material, and the investigation of new targeted nanoparticle-based PET/MRI agents