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Introduction 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.

Introduction Radioisotopes play an important role in nuclear medicine and represent powerful tools for imaging and therapy. With the extensive use of 99mTc-based imaging agents, therapeutic rhenium analogues are highly desirable. Rhenium-186 emits therapeutic − particles with an endpoint-energy of 1.07 MeV, allowing for a small, targeted tissue range of 3.6 mm. Additionally, its low abundance γ-ray emission of 137.2 keV (9.42 %) allows for in vivo tracking of a radiolabeled compounds and dosimetry calculations. With a longer half-life of 3.718 days, synthesis and shipment of Re-186 based radiopharmaceuticals is not limited. Rhenium-186 can be produced either in a reactor or in an accelerator. Currently, Re-186 is produced in a reactor via the 185Re(n,γ) reaction resulting in low specific activity which makes its therapeutic application limited.[1] Production in an accelerator, such as the PETtrace at the University of Missouri Research Reactor (MURR), can theoretically provide a specific activity of 34,600 Ci.mmol−1 Re[2], which represents a 62 fold increase over reactor produced 186Re. The studies reported herein focused on the evaluation of accelerator-based reaction pathways to produce high specific activity (HSA) 186Re. Those pathways include proton and deuteron bombardment of tungsten and osmium targets by the following reactions: 186W(p,n)186Re, 186W(d,2n) 186Re, 189Os(p,α)186Re, and 192Os(p,α3n)186Re. Additional information on target design related to the determination and optimization of production rates, radionuclidic purity, and yield are presented. Material and Methods Osmium and tungsten metals are very hard and thus very brittle. Attempts at pressing the pure metal into aluminum backings resulted in chalky targets, which easily crumbled during handling. Osmium disulfide (OsS2) and tungsten disulfide (WS2) were identified to provide a softer, less brittle chemical form for targets. OsS2 and WS2 targets were prepared using a unilateral press with a 13 mm diameter die to form pressed powder discs. A simple target holder design (FIG. 1) was implemented to provide a stabilizing platform for the pressed discs. The target material was sealed in place with epoxy using a thin aluminum foil pressed over the target face. Initial irradiations of OsS2 were performed using the 16 MeV GE PETtrace cyclotron at MURR. Irradiations were performed for 30–60 minutes with proton beam currents of 10–20 µA. Following irradiation, the OsS2 targets were dissolved in NaOCl and the pH adjusted using NaOH. The resultant aqueous solution was mixed with methyl ethyl ketone (MEK), with the lipophilic perrhenate being extracted into the MEK layer and the osmium and iridium remaining in the aqueous layer. The MEK extracts were then passed through an acidic alumina column to remove any remaining osmium and iridium. Determination of rhenium and iridium activities was done by gamma spectroscopy on an HPGe detector. Preliminary irradiations on WS2 targets were performed at MURR with the beam degraded to 14 MeV with a proton beam current of 10 µA for 60 minutes. After irradiation, WS2 was dissolved using 30% H2O2 with gentle heating and counted on an HPGe detector to determine the radio-nuclides produced. Results and Conclusion Thin natOsS2 targets were produced, irradiated at 16 MeV for 10 µAh, and analyzed for radiorhenium. Under these irradiation conditions, rhenium isotopes were produced in nanocurie quantities while iridium isotopes were produced in microcurie quantities. Future studies with higher proton energies are planned to increase the production of rhenium and decrease the production of iridium. After optimizing irradiation conditions, enriched 189Os will be used for irradiations to reduce the production of unwanted radionuclides. A liquid-liquid extraction method separated the bulk of the rhenium from the iridium. The majority of the rhenium produced was recovered in the first organic aliquot with little iridium observed while the majority of the iridium and osmium was retained in the first aqueous aliquot. Target production with WS2 was successful. A thin target of natWS2 was produced and irradiated at 14 MeV for 10 µAh. Under these irradiation conditions, several rhenium isotopes were produced in microcurie quantities. Target parameters to maximize 186Re production remain to be determined before enriched 186W targets are used for irradiations to reduce the production of unwanted radionuclides. In conclusion, the potential production routes for accelerator-produced high specific activity 186Re are being evaluated. Cyclotron-based irradiations of natOsS2 targets established the feasibility of producing rhenium via the natOs(p,αxn)Re reaction. Current results indicate higher proton energies are necessary to reduce the production of unwanted iridium isotopes while increasing the production of rhenium isotopes. Preliminary irradiations were performed using the 50.5 MeV Scanditronix MC50 clinical cyclotron at the University of Washington to determine irradiation parameters for future higher energy irradiations (20–30 MeV). A rapid liquid-liquid extraction method isolated rhenium from the bulk of the iridium and osmium following irradiation. Preliminary studies indicate WS2 may also provide a suitable target material to produce 186Re via the (p,n) reaction pathway.

Rhenium-186 has a half-life (t1/2 = 3.72 days) and emission of both gamma and beta particles that make it very attractive for use as a theranostic agent in targeted radionuclide therapy. 186Re can be readily prepared by the 185Re(n,γ)186Re reac-tion1. However, that reaction results in low specific activity, severely limiting the use of reactor produced 186Re in radiopharmaceuticals. It has previously been shown that high specific activity 186Re can be produced by cyclotron irradiations of 186W with protons and deuterons2,3. In this investigation we evaluated the 186W(d,2n)186Re reaction using thick target irradiations at higher incident deuteron energies and beam currents than previously reported. We elected not to use copper or aluminum foils in the preparation of our 186W targets due to their activation in the deuteron beam, so part of the investigation was an evaluation of an alternate method for preparing thick targets that withstand μA beam currents. Irradiation of 186W. Initial thick targets (~600-1100 mg) were prepared using 96.86% enriched 186W by hydraulic pressing (6.9 MPa) of tungsten metal powder into an aluminum target support. Those thick targets were irradiated for 10 minu-tes at 10 µA with nominal extracted deuteron energies of 15, 17, 20, 22, and 24 MeV. Isolation of 186Re. Irradiated targets were dissolved with H2O2 and basified with (NH4)2CO3 prior to separation using column(s) of ~100–300 mg Analig Tc-02 resin. Columns were washed with (NH4)2CO3 and the rhenium was eluted with ~80˚C H2O. Gamma-ray spectroscopy was per-formed to assess production yields, extraction yields, and radionuclidic byproducts. Recycling target material. When tested on a natural abundance W target, recovery of the oxidized WO4- target material from the resin was found to proceed rapidly with the addition of 4M HCl in the form of hydrated WO3. The excess water in the WO3 was then removed by calcination at 800 °C for 4 hours. This material was found to undergo reduction to metallic W at elevated temperatures (~1550 °C) in a tube furnace under an inert atmosphere (Ar). Quanti-fication of % reduction and composition analyses were accomplished with SEM, EDS, and XRD and were used to characterize and compare both the WO3 and reduced Wmetal products to a sample of commercially available material. Structural enhancement by surface annealing. In some experiments ~1 g WO3 pellets were prepared from Wmetal that had been chemically treated to simulate the target material recovery process described above. Following calcination, the WO3 was allowed to cool to ambient temperature, pulverized with a mortar and pestle and then uniaxially pressed at 13.8 MPa into 13 mm pellets. Conversion of the WO3 back to Wmetal in pellet form was accomplished in a tube furnace under flowing Ar at 1550 °C for 8 hours. Material characterization and product composition analyses were conducted with SEM, EDS, and XRD spectroscopy. Graphite-encased W targets. Irradiations were conducted at 20 μA with a nominal extracted deuteron energy of 17 MeV using thick targets (~750 mg) of natural abundance tungsten metal powder uniaxially pressed into an aluminum target support between layers of graphite pow-der (100 mg on top, 50 mg on the bottom). Targets were then dissolved as previously described and preliminary radiochemical isola-tion yields obtained by counting in a dose calibrator. Although irradiations of W targets were possible at 10 μA currents, difficulties were encountered in maintaining the structural integrity of the full-thickness pressed target pellets under higher beam currents. This led to further investigation of the target design for irradiations conducted at higher beam currents. Comprehensive target material characterization via analysis by SEM, EDS, XRD, and Raman Spectroscopy allowed for a complete redesign of the target maximizing the structural integrity of the pressed target pellet without impacting production or isolation. At the 10 A current, target mass loss following irradiation of an enriched 186W target was < 1 % and typical separation yields in excess of 70 % were observed. Saturated yields and percent of both 183Re (t½ = 70 days) and 184gRe (t½ = 35 days) relative to 186gRe (decay corrected to EOB) are reported in TABLE 1 below. The reason for the anomalously low yield at 24 MeV is unknown, but might be explained by poor beam alignment and/or rhenium volatility during irradiation. Under these irradiation conditions, recovery yields of the W target material from the recycling process were found to be in excess of 90% with no discernable differences noted when compared to commercially available Wmetal and WO3. Conceptually, increasing the structural integrity of pressed WO3 targets by high temperature heat treatment under an inert atmosphere is intriguing. However, the treated pellets lacked both density and structural stability resulting in disintegration upon manipulation , despite the initially encouraging energy dispersive X-ray spectroscopy (EDS) determination that 94.9% percent of the WO3 material in each pellet had been reduced to metallic W. The use of powdered graphite as a target stabi-lizing agent provided successful irradiation of natural abundance W under conditions where non-stabilized targets failed (20 µA at 17 MeV for 10 minutes). Target mass loss following irradiation of a natW target was < 1 % and a separation yield in excess of 97 % was obtained. In conclusion, the theranostic radionuclide 186Re was produced in thick targets via the 186W(d,2n) reaction. It was found that pressed W metal could be used for beam currents of 10 μA or less. For deuteron irradiations at higher beam currents, a method involving pressing W metal between two layers of graphite provides increased target stability. Both target configurations allow high recovery of radioactivity from the W target material, and a solid phase extraction method allows good recovery of 186Re. An effective approach to the recycling of enriched W has been developed using elevated temperature under an inert atmosphere. Further studies are underway with 186W targets sandwiched by graphite to assess 186Re production yields, levels of contaminant radiorhenium, power deposition, and enriched 186W material requirements under escalated irradiation conditions (20 µA and 17 MeV for up to 2 hours).