Production and separation of 7Be for use in an ion source.

Beryllium-7 (7Be) was created by proton irradiation of natural (natB) and enriched (10B) boron targets. The targets were dissolved in nitric acid, and the 7Be was separated from the bulk boron target material by cation-exchange chromatography. An average recovery of (99.4 ± 3.7)% was obtained for 6 separations. The purified 7Be sample was placed into a batch-mode ion source to create a 7Be beam that was delivered at an average rate of 5 × 105 pps to end users at the National Superconducting Cyclotron Laboratory.

Preparation of stable and long-lived source samples for the stand-alone beam program at the Facility for Rare Isotope Beams.

At the Facility for Rare Isotope Beams (FRIB), an oven-ion source combination was used to create rare isotope beams in support of the stand-alone user beam program of the ReAccelerator (ReA) facility. This ion source, called Batch-Mode Ion Source (BMIS), was loaded with enriched stable nuclides (30Si, 50Cr, and 58Fe) and long-lived radionuclides (26Al, 32Si). The introduced samples, herein designated as source samples, were thermally volatilized in the BMIS oven, and then ionization was used to generate the required beams. Owing to the different chemical behavior of the used samples, it was important to tailor the sample loading process for each desired beam species. An important parameter here is the volatility of the introduced species, which influences the adequate release of the isotope of interest. Additionally, any co-present, volatile components will affect the ion yields of the desired isotope, while isobaric contaminants will decrease the beam purity. To manufacture isotope source samples that meet these characteristics, various chemical methodologies were developed. All prepared samples were successfully used in BMIS to deliver beams for various user beam experiments. The here-established sample preparation techniques will greatly aid future efforts in developing offline rare-isotope beams.

Proof-of-concept studies of novel protocols for producing highly pure 48V from a 48Cr/48V generator.

The quest to improve the quality of nuclear data, such as half-lives, transition yields, and reaction cross-sections, is a shared endeavor among various areas of nuclear science. 48V is a vanadium isotope for which experimental data on neutron reaction cross-sections is needed. However, traditional isotope production techniques cannot produce 48V with high enough isotopic purity for some of these measurements. "Isotope harvesting" at the Facility for Rare Isotope Beams (FRIB) is a new isotope production technique that could potentially yield 48V with the necessary purity for such studies. In this case, 48Cr would be collected and allowed to generate 48V that can be separated from undecayed 48Cr to yield highly pure 48V. Thus, any protocol for producing pure 48V via isotope harvesting would involve utilizing a separation technique that can effectively separate 48Cr and 48V. In this study, the radiotracers 51Cr and 48V were used to develop possible radiochemical separation methodologies, which can be translated to obtain high purity 48V via this novel isotope production method. The developed protocols utilize either ion exchange or extraction chromatographic resins. Separations of 51Cr and 48V with AG 1-X8 anion exchange resin respectively resulted in recoveries of 95.6(26)% and 96.2(12)% with radionuclidic purities of 92(2)% and 99(1)%. An even more effective Cr and V separation was obtained with an extraction chromatographic resin (TRU resin) and 10 M HNO3 loading solution. Here, 51Cr and 48V respectively had recoveries of 94.1(28)% and 96.2(13)% with high radionuclidic purities (100(2)% and 100(1)%) in small volumes (8.81(8) mL and 5.39(16) mL). This study suggests that, to maximize the yield and isotopic purity of 48V, the best production protocol would involve utilizing two separations with TRU resin and 10 M HNO3 to isolate 48Cr and purify the generated 48V.

Harvesting 88Zr from heavy-ion beam irradiated tungsten at the National Superconducting Cyclotron Laboratory.

Tungsten is a commonly used material at many heavy-ion beam facilities, and it often becomes activated due to interactions with a beam. Many of the activation products are useful in basic and applied sciences if they can be recovered efficiently. In order to develop the radiochemistry for harvesting group (IV) elements from irradiated tungsten, a heavy-ion beam containing 88Zr was embedded into a stack of tungsten foils at the National Superconducting Cyclotron Laboratory and a separation methodology was devised to recover the 88Zr. The foils were dissolved in 30% hydrogen peroxide, and the 88Zr was chemically purified from the tungsten matrix and from other co-implanted radionuclides (such as 85Sr and 88Y) using strong cation-exchange (AG MP-50) chromatographic resin in sulfuric acid media. The procedure provided 88Zr in approximately 60 mL 0.5 M sulfuric acid with no detectable radio-impurities. The overall recovery yield for 88Zr was (92.3 ± 1.2)%. This proof-of-concept experiment has facilitated the development of methodologies to harvest from tungsten and tungsten-alloy parts that are regularly irradiated at heavy-ion beam facilities.

Solid-phase isotope harvesting of 88Zr from a radioactive ion beam facility.

During routine operation of the Facility for Rare Isotope Beams (FRIB), radionuclides will accumulate in both the aqueous beam dump and along the beamline in the process of beam purification. These byproduct radionuclides, many of which are far from stability, can be collected and purified for use in other scientific applications in a process called isotope harvesting. In this work, the viability of 88Zr harvesting from solid components was investigated at the National Superconducting Cyclotron Laboratory. A secondary 88Zr beam was stopped in a series of collectors comprised of Al, Cu, W, and Au foils. This work details irradiation of the collector foils and the subsequent radiochemical processing to isolate the deposited 88Zr (and its daughter 88Y) from them. Total average recovery from the Al, Cu, and Au collector foils was (91.3 ± 8.9) % for 88Zr and (95.0 ± 5.8) % for 88Y, respectively, which is over three times higher recovery than in a previous aqueous-phase harvesting experiment. The utility of solid-phase isotope harvesting to access elements such as Zr that readily hydrolyze in near-neutral pH aqueous conditions has been demonstrated for application to harvesting from solid components at FRIB.

A Model for Radiolysis in a Flowing-Water Target during High-Intensity Proton Irradiation.

At the Facility for Rare Isotope Beams (FRIB), interactions between heavy-ion beams and beam-dump water will create a wide variety of radionuclides which can be accessed by a technique known as "isotope harvesting". However, irradiation of water is always accompanied by the creation of numerous radical, ionic, and molecular radiolysis products. Some of the radiolysis products have sufficiently long lifetimes to accumulate in the irradiated water and affect the harvesting chemistry. Here we investigate the formation of hydrogen peroxide, molecular hydrogen, and molecular oxygen during a high-intensity proton irradiation of a flowing-water isotope-harvesting target and compare the experimental results to simulations. The simulations kinetically model the chemical reactions occurring in the homogeneous phase of radiolysis in flowing water and establish an "effective yield". In both the experiment and simulations, the bulk quantities of H2, H2O2, and O2 are considerably lower than predicted by primary radiolysis yields (escape yields), meaning that in the high beam intensity regime the homogeneous phase reactions have a considerable impact on the overall chemical composition of the water. Further, it could be shown that for radiation which is characterized by a limited linear energy transfer, such as the here applied protons, the bulk outcome of the microscopic kinetic modeling could be estimated by a simplified steady-state model.

Harvesting krypton isotopes from the off-gas of an irradiated water target to generate 76Br and 77Br.

A flowing-water target was irradiated with a 150 MeV/nucleon beam of 78Kr at the National Superconducting Cyclotron Laboratory to produce 77Kr and 76Kr. Real-time gamma-imaging measurements revealed the mass transport of the krypton radioisotopes through the target-water processing, or "isotope harvesting", system. The production rates were determined to be 2.7(1) × 10-4 nuclei of 76Kr and 1.18(6) × 10-2 nuclei of 77Kr formed per incident 78Kr ion. Utilizing an off-gas processing line as part of the isotope harvesting system, a total of 7.2(1) MBq of 76Kr and 19.1(6) MBq of 77Kr were collected in cold traps. Through the decay, the daughter radionuclides 76Br and 77Br were generated and removed from the traps with an average efficiency of 77 ± 12%. Due to the differences in half-lives of 76Kr and 77Kr, it was possible to isolate a pure sample of 76Br with 99.9% radionuclidic purity. The successful collection of krypton radioisotopes to generate 76Br and 77Br demonstrates the feasibility of gas-phase isotope harvesting from irradiated accelerator cooling-water. Larger-scale collections are planned for collecting by-product radionuclides from the Facility for Rare Isotope Beams.

Therapeutic Potential of 47Sc in Comparison to 177Lu and 90Y: Preclinical Investigations.

Targeted radionuclide therapy with 177Lu- and 90Y-labeled radioconjugates is a clinically-established treatment modality for metastasized cancer. 47Sc is a therapeutic radionuclide that decays with a half-life of 3.35 days and emits medium-energy ß--particles. In this study, 47Sc was investigated, in combination with a DOTA-folate conjugate, and compared to the therapeutic properties of 177Lu-folate and 90Y-folate, respectively. In vitro, 47Sc-folate demonstrated effective reduction of folate receptor-positive ovarian tumor cell viability similar to 177Lu-folate, but 90Y-folate was more potent at equal activities due to the higher energy of emitted ß--particles. Comparable tumor growth inhibition was observed in mice that obtained the same estimated absorbed tumor dose (~21 Gy) when treated with 47Sc-folate (12.5 MBq), 177Lu-folate (10 MBq), and 90Y-folate (5 MBq), respectively. The treatment resulted in increased median survival of 39, 43, and 41 days, respectively, as compared to 26 days in untreated controls. There were no statistically significant differences among the therapeutic effects observed in treated groups. Histological assessment revealed no severe side effects two weeks after application of the radiofolates, even at double the activity used for therapy. Based on the decay properties and our results, 47Sc is likely to be comparable to 177Lu when employed for targeted radionuclide therapy. It may, therefore, have potential for clinical translation and be of particular interest in tandem with 44Sc or 43Sc as a diagnostic match, enabling the realization of radiotheragnostics in future.

Scandium and terbium radionuclides for radiotheranostics: current state of development towards clinical application.

Currently, different radiometals are in use for imaging and therapy in nuclear medicine: 68Ga and 111In are examples of nuclides for positron emission tomography (PET) and single photon emission computed tomography (SPECT), respectively, while 177Lu and 225Ac are used for ß-- and α-radionuclide therapy. The application of diagnostic and therapeutic radionuclides of the same element (radioisotopes) would utilize chemically-identical radiopharmaceuticals for imaging and subsequent treatment, thereby enabling the radiotheranostic concept. There are two elements which are of particular interest in this regard: Scandium and Terbium. Scandium presents three radioisotopes for theranostic application. 43Sc (T1/2 = 3.9 h) and 44Sc (T1/2 = 4.0 h) can both be used for PET, while 47Sc (T1/2 = 3.35 d) is the therapeutic match-also suitable for SPECT. Currently, 44Sc is most advanced in terms of production, as well as with pre-clinical investigations, and has already been employed in proof-of-concept studies in patients. Even though the production of 43Sc may be more challenging, it would be advantageous due to the absence of high-energetic γ-ray emission. The development of 47Sc is still in its infancy, however, its therapeutic potential has been demonstrated preclinically. Terbium is unique in that it represents four medically-interesting radioisotopes. 155Tb (T1/2 = 5.32 d) and 152Tb (T1/2 = 17.5 h) can be used for SPECT and PET, respectively. Both radioisotopes were produced and tested preclinically. 152Tb has been the first Tb isotope that was tested (as 152Tb-DOTATOC) in a patient. Both radionuclides may be of interest for dosimetry purposes prior to the application of radiolanthanide therapy. The decay properties of 161Tb (T1/2 = 6.89 d) are similar to 177Lu, but the coemission of Auger electrons make it attractive for a combined ß-/Auger electron therapy, which was shown to be effective in preclinical experiments. 149Tb (T1/2 = 4.1 h) has been proposed for targeted α-therapy with the possibility of PET imaging. In terms of production, 161Tb and 155Tb are most promising to be made available at the large quantities suitable for future clinical translation. This review article is dedicated to the production routes, the methods of separating the radioisotopes from the target material, preclinical investigations and clinical proof-of-concept studies of Sc and Tb radionuclides. The availability, challenges of production and first (pre)clinical application, as well as the potential of these novel radionuclides for future application in nuclear medicine, are discussed.

47Sc as useful ß--emitter for the radiotheragnostic paradigm: a comparative study of feasible production routes.

BACKGROUND: Radiotheragnostics makes use of the same molecular targeting vectors, labeled either with a diagnostic or therapeutic radionuclide, ideally of the same chemical element. The matched pair of scandium radionuclides, 44Sc and 47Sc, satisfies the desired physical aspects for PET imaging and radionuclide therapy, respectively. While the production and application of 44Sc was extensively studied, 47Sc is still in its infancy. The aim of the present study was, therefore, to investigate and compare two different methods of 47Sc production, based on the neutron irradiation of enriched 46Ca and 47Ti targets, respectively. METHODS: 47Sc was produced by thermal neutron irradiation of enriched 46Ca targets via the 46Ca(n,γ)47Ca → 47Sc nuclear reaction and by fast neutron irradiation of 47Ti targets via the 47Ti(n,p)47Sc nuclear reaction, respectively. The product was compared with regard to yield and radionuclidic purity. The chemical separation of 47Sc was optimized in order to obtain a product of sufficient quality determined by labeling experiments using DOTANOC. Finally, preclinical SPECT/CT experiments were performed in tumor-bearing mice and compared with the PET image of the 44Sc labeled counterpart. RESULTS: Up to 2 GBq 47Sc was produced by thermal neutron irradiation of enriched 46Ca targets. The optimized chemical isolation of 47Sc from the target material allowed formulation of up to 1.5 GBq 47Sc with high radionuclidic purity (>99.99%) in a small volume (~700 µL) useful for labeling purposes. Three consecutive separations were possible by isolating the in-grown 47Sc from the 46/47Ca-containing fraction. 47Sc produced by fast neutron irradiated 47Ti targets resulted in a reduced radionuclidic purity (99.95-88.5%). The chemical purity of the separated 47Sc was determined by radiolabeling experiments using DOTANOC achievable at specific activities of 10 MBq/nmol. In vivo the 47Sc-DOTANOC performed equal to 44Sc-DOTANOC as determined by nuclear imaging. CONCLUSION: The production of 47Sc via the 46Ca(n,γ)47Ca nuclear reaction demonstrated significant advantages over the 47Ti production route, as it provided higher quantities of a radionuclidically pure product. The subsequent decay of 47Ca enabled the repeated separation of the 47Sc daughter nuclide from the 47Ca parent nuclide. Based on the results obtained from this work, 47Sc shows potential to be produced in suitable quality for clinical application.

Production and separation of 43Sc for radiopharmaceutical purposes.

BACKGROUND: The favorable decay properties of 43Sc and 44Sc for PET make them promising candidates for future applications in nuclear medicine. An advantage 43Sc (T1/2 = 3.89 h, Eß+av = 476 keV [88%]) exhibits over 44Sc, however, is the absence of co-emitted high energy γ-rays. While the production and application of 44Sc has been comprehensively discussed, research concerning 43Sc is still in its infancy. This study aimed at developing two different production routes for 43Sc, based on proton irradiation of enriched 46Ti and 43Ca target material. RESULTS: 43Sc was produced via the 46Ti(p,α)43Sc and 43Ca(p,n)43Sc nuclear reactions, yielding activities of up to 225 MBq and 480 MBq, respectively. 43Sc was chemically separated from enriched metallic 46Ti (97.0%) and 43CaCO3 (57.9%) targets, using extraction chromatography. In both cases, ~90% of the final activity was eluted in a small volume of 700 µL, thereby, making it suitable for direct radiolabeling. The prepared products were of high radionuclidic purity, i.e. 98.2% 43Sc were achieved from the irradiation of 46Ti, whereas the product isolated from irradiated 43Ca consisted of 66.2% 43Sc and 33.3% 44Sc. A PET phantom study performed with 43Sc, via both nuclear reactions, revealed slightly improved resolution over 44Sc. In order to assess the chemical purity of the separated 43Sc, radiolabeling experiments were performed with DOTANOC, attaining specific activities of 5-8 MBq/nmol, respectively, with a radiochemical yield of >96%. CONCLUSIONS: It was determined that higher 43Sc activities were accessible via the 43Ca production route, with a comparatively less complex target preparation and separation procedure. The product isolated from irradiated 46Ti, however, revealed purer 43Sc with minor radionuclidic impurities. Based on the results obtained herein, the 43Ca route features some advantages (such as higher yields and direct usage of the purchased target material) over the 46Ti path when aiming at 43Sc production on a routine basis.

44Sc for labeling of DOTA- and NODAGA-functionalized peptides: preclinical in vitro and in vivo investigations.

BACKGROUND: Recently, 44Sc (T1/2 = 3.97 h, Eß+av = 632 keV, I = 94.3 %) has emerged as an attractive radiometal candidate for PET imaging using DOTA-functionalized biomolecules. The aim of this study was to investigate the potential of using NODAGA for the coordination of 44Sc. Two pairs of DOTA/NODAGA-derivatized peptides were investigated in vitro and in vivo and the results obtained with 44Sc compared with its 68Ga-labeled counterparts.DOTA-RGD and NODAGA-RGD, as well as DOTA-NOC and NODAGA-NOC, were labeled with 44Sc and 68Ga, respectively. The radiopeptides were investigated with regard to their stability in buffer solution and under metal challenge conditions using Fe3+ and Cu2+. Time-dependent biodistribution studies and PET/CT imaging were performed in U87MG and AR42J tumor-bearing mice. RESULTS: Both RGD- and NOC-based peptides with a DOTA chelator were readily labeled with 44Sc and 68Ga, respectively, and remained stable over at least 4 half-lives of the corresponding radionuclide. In contrast, the labeling of NODAGA-functionalized peptides with 44Sc was more challenging and the resulting radiopeptides were clearly less stable than the DOTA-derivatized matches. 44Sc-NODAGA peptides were clearly more susceptible to metal challenge than 44Sc-DOTA peptides under the same conditions. Instability of 68Ga-labeled peptides was only observed if they were coordinated with a DOTA in the presence of excess Cu2+. Biodistribution data of the 44Sc-labeled peptides were largely comparable with the data obtained with the 68Ga-labeled counterparts. It was only in the liver tissue that the uptake of 68Ga-labeled DOTA compounds was markedly higher than for the 44Sc-labeled version and this was also visible on PET/CT images. The 44Sc-labeled NODAGA-peptides showed a similar tissue distribution to those of the DOTA peptides without any obvious signs of in vivo instability. CONCLUSIONS: Although DOTA revealed to be the preferred chelator for stable coordination of 44Sc, the data presented in this work indicate the possibility of using NODAGA in combination with 44Sc. In view of a clinical study, thorough investigations will be necessary regarding the labeling conditions and storage solutions in order to guarantee sufficient stability of 44Sc-labeled NODAGA compounds.

Cyclotron production of (44)Sc: From bench to bedside.

INTRODUCTION: (44)Sc, a PET radionuclide, has promising decay characteristics (T1/2 = 3.97 h, Eß(+)av = 632 keV) for nuclear imaging and is an attractive alternative to the short-lived (68)Ga (T1/2 = 68 min, Eß(+)av = 830 keV). The aim of this study was the optimization of the (44)Sc production process at an accelerator, allowing its use for preclinical and clinical PET imaging. METHODS: (44)CaCO3 targets were prepared and irradiated with protons (~11 MeV) at a beam current of 50 µA for 90 min. (44)Sc was separated from its target material using DGA extraction resin and concentrated using SCX cation exchange resin. Radiolabeling experiments at activities up to 500 MBq and stability tests were performed with DOTANOC by investigating different scavengers, including gentisic acid. Dynamic PET of an AR42J tumor-bearing mouse was performed after injection of (44)Sc-DOTANOC. RESULTS: The optimized chemical separation method yielded up to 2 GBq (44)Sc of high radionuclidic purity. In the presence of gentisic acid, radiolabeling of (44)Sc with DOTANOC was achieved with a radiochemical yield of ~99% at high specific activity (10 MBq/nmol) and quantities which would allow clinical application. The dynamic PET images visualized increasing uptake of (44)Sc-DOTANOC into AR42J tumors and excretion of radioactivity through the kidneys of the investigated mouse. CONCLUSIONS: The concept "from-bench-to-bedside" was clearly demonstrated in this extended study using cyclotron-produced (44)Sc. Sufficiently high activities of (44)Sc of excellent radionuclidic purity are obtainable for clinical application, by irradiation of enriched calcium at a cyclotron. This work demonstrates a promising basis for introducing (44)Sc to clinical routine of nuclear imaging using PET.