IBA Cyclone Research Articles

Improved Production of Novel Radioisotopes with Custom Energy Cyclone® Kiube

The implementation of the Variable Energy (VE) feature in the previously fixed-energy IBA Cyclone® Kiube cyclotron is presented as an upgrade enabling the production of novel radioisotopes with improved radionuclidic purity and production yields. The possibility of easily decreasing the energy of the extracted proton beam, from 18 down to 13 MeV, allows us to avoid the use of degraders and/or thick target windows, thus preventing related beam current limitations. The immediate application of the Variable Energy feature is proven by presenting the improved results obtained for the production of 68Ga from the irradiation of liquid targets simultaneously in terms of radionuclidic purity and activity produced.

Analysis of the accumulation of β-emitting radionuclides in the production of radiopharmaceuticals based on <sup>18</sup>F using the IBA CYCLONE 18/9 HC cyclotron

In order to clarify the scheme of radioactive waste management, the accumulation of undesirable beta-emitting radionuclides (PH) in the production of radiopharmaceuticals based on 18F using the IBA CYCLONE 18/9 HC cyclotron was investigated. It is shown that the dominant impurity PH is tritium, which is formed by the reaction of 18O(p, t) 16O when water is irradiated with [18O]H2O protons. The main proportion of 3H (about 95%) remains in the regenerated water. 1.6 % of the accumulated tritium activity is carried away from the synthesis zone with gases and water vapor. Tritium-containing waste (regenerated water in vials) can be considered as waste of a very low level of activity during disposal. With an increase in the operating time of the target over 2500 µA · h, the processes of corrosion /erosion of target materials increase, which leads to a sharp increase in the concentration of undesirable radionuclides in regenerated water, sorption purification cartridges and the finished dosage form. The concentration of tritium does not increase significantly. In the β-spectra of regenerated water [18O]H2O and the finished radiopharmaceutical [18F]NaF, in addition to the maximum due to tritium, a number of maxima appear in both the low- and high-energy parts of the spectrum. Other undesirable β-emitters accumulate in water as a result of leaching of the activated target wall. The possibility of using measurements of tritium activity in water [18O]H2O as an indicator of its re-enrichment has been demonstrated. The necessity of controlling the content of impurity beta-emitting PH in intermediate products, production waste and final radiopharmaceutical is shown.

Monte Carlo simulations of microdosimetry and radiolytic species production at long time post proton irradiation using GATE and Geant4-DNA.

Radiobiological effectiveness of radiation in cancer treatment can be studied at different scales (molecular till organ scale) and different time post irradiation. The production of free radicals and reactive oxygen species during water radiolysis is particularly relevant to understand the fundamental mechanisms playing a role in observed biological outcomes. The development and validation of Monte Carlo tools integrating the simulation of physical, physico-chemical and chemical stages after radiation is very important to maintain with experiments. Therefore, in this study, we propose to validate a new Geant4-DNA chemistry module through the simulation of water radiolysis and Fricke dosimetry experiments on a proton preclinical beam line. In this study, we used the GATE Monte Carlo simulation platform (version 9.3) to simulate a 67.5 MeV proton beam produced with the ARRONAX isochronous cyclotron (IBA Cyclone 70XP) at conventional dose rate (0.2Gy/s) to simulate the irradiation of ultra-pure liquid water samples and Fricke dosimeter. We compared the depth dose profile with measurements performed with a plane parallel Advanced PTW 34045 Markus ionization chamber. Then, a new Geant4-DNA chemistry application proposed from Geant4 version 11.2 has been used to assess the evolution of , , , , , , and reactive species along time until 1-h post-irradiation. In particular, the effect of oxygen and pH has been investigated through comparisons with experimental measurements of radiolytic yields for and Fe3+. GATE simulations reproduced, within 4%, the depth dose profile in liquid water. With Geant4-DNA, we were able to reproduce experimental radiolytic yields 1-h post-irradiation in aerated and deaerated conditions, showing the impact of small changes in oxygen concentrations on species evolution along time. For the Fricke dosimeter, simulated G(Fe3+) is 15.97±0.2 molecules/100eV which is 11% higher than the measured value (14.4±04 molecules/100 eV). These results aim to be consolidated by new comparisons involving other radiolytic species, such as or to further study the mechanisms underlying the FLASH effect observed at ultra-high dose rates (UHDR).

Neurotensin (8-13) and Neuromedin N Neuropeptides Radiolabelling with Copper-64 Produced on Solid or Liquid Targets.

On the verge of a theranostic approach to personalised medicine, copper-64 is one of the emerging radioisotopes in nuclear medicine due to its exploitable nuclear and biochemical characteristics. The increased demand for copper-64 for preclinical and clinical studies has prompted the development of production routes. This research aims to compare the (p,n) reaction on nickel-64 solid versus liquid targets and evaluate the effectiveness of [64Cu]CuCl2 solutions prepared by the two routes. As new treatments for neurotensin receptor-overexpressing tumours have developed, copper-64 was used to radiolabel Neurotensin (8-13) and Neuromedin N. High-quality [64Cu]CuCl2 solutions were prepared using ACSI TR-19 and IBA Cyclone Kiube cyclotrons. The radiochemical purity after post-irradiation processing reached 99% (LT) and 99.99% (ST), respectively. The irradiation of a solid target with 11.8 MeV protons and 150 μAh led to 704 ± 84 MBq/μA (17.6 ± 2.1 GBq/batch at EOB). At the end of the purification process (1 h, 90.90% activity yield), the solution for peptide radiolabelling had a radioactive concentration of 1340.4 ± 70.1 MBq/mL (n.d.c.). The irradiation of a liquid target with 16.9 MeV protons and 230 μAh resulted in 3.7 ± 0.2 GBq/batch at EOB, which corresponds to an experimental production yield of 6.89 GBq.cm3/(g.µA)sat. Benefiting from a shorter purification process (40 min), the activity yielded 90.87%, while the radioactive concentration of the radiolabelling solution was lower (492 MBq/mL, n.d.c.). The [64Cu]CuCl2 solutions were successfully used for the radiolabelling of DOTA-NT(8-13) and DOTA-NN neuropeptides, resulting in a high RCP (>99%) and high molar activity (27.2 and 26.4 GBq/μmol for LT route compared to 45 and 52 GBq/μmol for ST route, respectively). The strong interaction between the [64Cu]Cu-DOTA-NT(8-13) and the colon cancerous cell lines HT29 and HCT116 proved that the specificity for NTR had not been altered, as shown by the uptake and retention data.

On radiation situation in vicinity of PET production cyclotron

The medical cyclotrons intended for the production of medical isotopes are relatively widespread. The most common radioisotope product of these facilities is 18F which origins from 18O(p, n)18F reaction. Due to relatively large amounts of produced nuclei, the leakage neutron and gamma flux is a big issue in radiation safety in such cyclotron labs. Due to relatively high energies of accelerated protons, high energy gammas and neutrons are produced with energies above 10 MeV with high penetration properties. Neutron and gamma spectra around cyclotron IBA Cyclone 18/9 intended for production of 18F was measured with stilbene detector. It was compared to simulated neutron spectra with various Monte Carlo codes and with spectral indices calculated from reaction rates in activation detectors. Strong disagreement in simulation of spectra in backward angles was found for MC codes Geant4 and MCNP6.2.

A combined approach for the calculation of activation yields and the characterization of materials for a medical cyclotron

Cyclotrons for the production of radiopharmaceuticals have become important tools in modern nuclear medicine. At the end of their lifecycles, such installations have to be dismantled and any activated materials must be treated according to the local radiation protection legislation. Using a simulation model, we have developed a non-destructive approach for the radiological characterization of components inside and around an IBA Cyclone 18/9 cyclotron. The methodology is based on software tools developed at CERN (FLUKA Monte Carlo code, ActiWiz and RAW). The simulation results were compared to measurements made using reference samples placed around the cyclotron inside the bunker. Results show a reasonable agreement between simulation and measurements of about a factor of two for a set of 27 reference samples and 11 radionuclides of interest. The origin of this factor has been thoroughly evaluated and opened the door to further investigations leading to possible avenues for improvement.

Antibody and Nanobody Radiolabeling with Copper-64: Solid vs. Liquid Target Approach.

Antibody and nanobody-based copper-64 radiopharmaceuticals are increasingly being proposed as theranostic tools in multiple human diseases. While the production of copper-64 using solid targets has been established for many years, its use is limited due to the complexity of solid target systems, which are available in only a few cyclotrons worldwide. In contrast, liquid targets, available in virtually in all cyclotrons, constitute a practical and reliable alternative. In this study, we discuss the production, purification, and radiolabeling of antibodies and nanobodies using copper-64 obtained from both solid and liquid targets. Copper-64 production from solid targets was performed on a TR-19 cyclotron with an energy of 11.7 MeV, while liquid target production was obtained by bombarding a nickel-64 solution using an IBA Cyclone Kiube cyclotron with 16.9 MeV on target. Copper-64 was purified from both solid and liquid targets and used to radiolabel NODAGA-Nb, NOTA-Nb, and DOTA-Trastuzumab conjugates. Stability studies were conducted on all radioimmunoconjugates in mouse serum, PBS, and DTPA. Irradiation of the solid target yielded 13.5 ± 0.5 GBq with a beam current of 25 ± 1.2 μA and an irradiation time of 6 h. On the other hand, irradiation of the liquid target resulted in 2.8 ± 1.3 GBq at the end of bombardment (EOB) with a beam current of 54.5 ± 7.8 μA and an irradiation time of 4.1 ± 1.3 h. Successful radiolabeling of NODAGA-Nb, NOTA-Nb, and DOTA-Trastuzumab with copper-64 from both solid and liquid targets was achieved. Specific activities (SA) obtained with the solid target were 0.11, 0.19, and 0.33 MBq/μg for NODAGA-Nb, NOTA-Nb, and DOTA-trastuzumab, respectively. For the liquid target, the corresponding SA values were 0.15, 0.12, and 0.30 MBq/μg. Furthermore, all three radiopharmaceuticals demonstrated stability under the testing conditions. While solid targets have the potential to produce significantly higher activity in a single run, the liquid process offers advantages such as speed, ease of automation, and the feasibility of back-to-back production using a medical cyclotron. In this study, successful radiolabeling of antibodies and nanobodies was achieved using both solid and liquid targets approaches. The radiolabeled compounds exhibited high radiochemical purity and specific activity, rendering them suitable for subsequent in vivo pre-clinical imaging studies.

Novel solid target and irradiation methods for theranostic radioisotope production at the Bern medical cyclotron

The production of medical radioisotopes for theranostics is essential for the development of personalized nuclear medicine. Among them, radiometals can be used to label proteins and peptides and their supply in quantity and quality suitable for clinical applications represents a scientific challenge. A research program is ongoing at the Bern medical cyclotron, where an IBA Cyclone 18/18 HC is in operation. The cyclotron provides 18 MeV proton beams up to 150 μA and is equipped with a Solid Target Station (STS) and a 6 m Beam Transport Line (BTL), ending in a separate bunker with independent access. A novel magnetic target coin was realized to bombard isotope-enriched materials in the form of compressed powders, together with a compact focalization system to enhance the irradiation procedure. For an optimized production yield with the required radionuclidic purity, novel methods were developed to precisely measure the extracted beam energy and the involved reaction cross sections. In particular, a target station was realized to measure nuclear cross sections using materials in the form of powder deposited on an aluminium disc by sedimentation, bombarded by a monitored flat beam.

Validation of calculational determination of 18O(p,n) secondary neutron field

Cyclotrons used to produce medical isotopes are relatively widespread. Nowadays, it is popular to place small and compact accelerators directly in hospitals. This approach simplifies handling of the produced radiopharmaceuticals, but it imposes strict radiation safety measures during production. For optimal utilization of isotope production cyclotrons, the exact knowledge of leakage neutron field is essential due to the deep penetration ability of the high energy neutrons and the accompanied secondary radiation production. Our paper presents measurement of the neutron leakage spectra for various angles from an open target assembly at the cyclotron U-120M at NPI of CAS. These spectra are compared with data obtained from a compact medical cyclotron IBA Cyclone 18/9 in UJV Rez and also with activation measurements of reactions with different threshold energies. All data were also compared with calculations made with different Monte Carlo codes using both models and data libraries. The preliminary results show significant disagreement between experiments and theoretical predictions. These findings could have implications not only to the nuclear data community but also to the production accelerators operators at the licensing stage.

Modelling cyclotron-based production of radioisotopes via TOPAS

Objective. In this work, the irradiation of natural titanium foils in the beam-stop of a compact medical cyclotron, an IBA CYCLONE 18/9, is simulated to assess the efficacy of using a beam-stop as a target holder, and using two different target geometries, in the production of vanadium-48, a positron-emitting radioisotope with potential utility as a cancer imaging agent in positron emission tomography. Approach. TOPAS, the TOol for PArticle Simulation, a Geant4-based Monte Carlo program, was used to model the cyclotron beam parameters, choose an appropriate physics list, and simulate the irradiation of targets made from foils of 12 or 12.5 μm thickness. These simulation yields were compared to theoretical yields calculated using cross section data from the literature, as well as assayed yields from experimental irradiations. Main results. We found that most physics lists in TOPAS overestimate the cross section in the desired energy range (16–20 MeV) by at least 136%, with the exception of those using the Bertini Cascade Model. Compared to assayed yields, TOPAS provided a minimum of 0.4% error for cup-shaped targets and at least a 12% overestimation for sphere-shaped targets. Significance. These simulations provide a tool to help explain irregularities in radioisotope production yield and motivate modifications to increase target yield.

ACCUMULATION OF RADIONUCLIDES IN REPLACEABLE PARTS AND WATER TARGET CYCLOTRON

The accumulation of unwanted long-lived radionuclides during the production of 18F-based radiopharmaceuticals using the IBA Cyclone 18/9 HC cyclotron is considered. Using high-resolution gamma-ray spectrometry with HPGe detectors, the identification of radionuclides and the assessment of activity in activated components (stripper, target entrance window) of the "medical" 18-MeV cyclotron IBA Cyclone 18/9 were carried out. More than 20 unwanted radionuclides have been identified in irradiated water. Various mechanisms for the entry of longlived radionuclides into irradiated water are described. The results obtained are of great importance for optimizing the methods of radioactive waste management in the production of radiopharmaceuticals and, as a result, minimizing the radiation exposure of personnel.

Decommissioning procedure and induced activation levels, calculations and measurements in an 18 MeV medical cyclotron

The present article describes the decommissioning of a self-shielded 18 MeV medical cyclotron IBA Cyclone 18/9 after 14 years of operation. A Monte Carlo simulation of the possible nuclear reactions was performed in order to plan the decommissioning activities. During the cyclotron dismantling, the activities of the cyclotron components, concrete wall and floor samples were measured. Residual activities were analysed by means of an HPGe detector and liquid scintillation counting, and compared with simulation data. Dosimetry of the staff involved in the decommissioning procedure was monitored by individual TL dosimeters and/or digital dosimeter. The cyclotron component analysis confirmed the presence of gamma and pure beta emitters, 22Na, 54Mn, 60Co, 65Zn, 207Bi, 55Fe, 63Ni at different values of specific activity, depending on the positioning of the sample point and on the alloy of the sampled part. In these components the presence of gamma and pure beta emitters was measured 5 years after the shutdown at levels far above clearance limits as defined by the ‘Recommended radiological protection criteria for the recycling of metals from the dismantling of nuclear installations’ (RP89) guidelines. The simulation, carried out by FLUKA Code (version 2020.0.5) on the cyclotron components, provided good agreement with measurements, with a maximum discrepancy of the same order as the uncertainties. Four engineers of the cyclotron maintenance staff were involved in the dismounting of the hottest components and rigging of the cyclotron in the deposit 6 months after shutdown and two engineers were involved during the drilling phase 3.5 years after shutdown. The measured dose from external exposure of the involved staff was lower than 100 μSv person−1 during the first phase and lower than 20 μSv person−1 during the final drilling phase. Measured doses from intake were negligible. In conclusion, the decommissioning of the 18 MeV cyclotron does not represent a risk for the involved staff, but, due to the presence of long-lived radioisotopes, the cyclotron components are to be treated as low level radioactive waste, and stored in an authorised storage area for at least 25 years after shutdown.

Radiation-induced effects in glass windows for optical readout GEM-based detectors

In this paper we present irradiation measurements performed to select a transparent anode substrate that best meets the requirements of an optical readout for a novel detector, the LaGEMPix. The modification of the optical properties of the material due to proton irradiation were studied in soda-lime, fused quartz and fused silica glasses coated with an Indium Tin Oxide layer. The irradiations were performed using the research Beam Transfer Line (BTL) of the IBA Cyclone 18 MeV cyclotron of the Bern University Hospital (Inselspital). We recorded visible scintillation light generated by proton irradiation in the soda-lime and fused quartz samples. We also investigated the darkening of these three glasses and observed radiation-induced colour centres in the soda-lime glass sample. The optical transmission spectra of the samples were measured before and after irradiation. Reductions of 45%, 1% and 0.4% were observed for soda-lime glass, fused quartz and fused silica, respectively (with an associated error of 0.25%). We conclude that the best option for our specific application is the fused silica substrate, which will be the transparent anode for the next generation of the LaGEMPix detector.

Activation studies for the decommissioning of PET cyclotron bunkers by means of Monte Carlo simulations

During the operational life of a PET cyclotron, the concrete walls of the vault are activated by secondary neutrons. For the dismantling of such accelerator facilities, a considerable amount of low level solid radioactive waste has to be characterized and disposed. To decrease future dismantling costs and complexity, the amount of radioactive waste has to been prospectively evaluated in the design phase, then confirmed at the time of planning decommissioning. In this work, the Monte Carlo code Fluka was used for the assessment of the activation of the bunkers of two different facilities: the 16.5 MeV GE PETtrace at S. Orsola-Malpighi Hospital in Bologna and the 18 MeV IBA Cyclone 18/18 HC at the Bern University Hospital (Inselspital). The simulations were validated by means of experimental measurements performed in our previous works: non-destructive, in field measurements using a portable CZT detector were performed in Bologna; while core drilling samples were extracted from the bunker and measured in laboratory with an HPGe detector in Bern. The activity of the most important radionuclides in the concrete walls of the bunker, namely Eu-152, Mn-54, Co-60, Sc-46, Zn-65 and Cs-134 resulted within the range of 0.01 – 2 Bq/g. The consistency between Monte Carlo results and experimental measurements was within a factor 2 - 3 for most radionuclides, except for Eu-152, Sc-46, Zn-65. The activity concentrations estimated at each position considered exceeds the clearance levels of the new Directive 2013/59/Euratom.The results of this work demonstrate that Monte Carlo simulations based on FLUKA are adequate to assess the residual activation levels, a fundamental information to foresee, plan and optimize the decommissioning of a cyclotron based PET centers.

The methodology of characterization of neutron leakage field from PET production cyclotron for experimental purposes

During the production of 18F isotope for radiopharmaceuticals in 18O(p,n)18F reactions, the leakage neutrons are mostly considered as a waste product. The utilization of a cyclotron based neutron source might be an interesting application because its average energy is relatively high and emissivity is quite strong. Thus its use might be useful in many fields of neutron based research. This paper aims to define the methodology and its following use for the characterization of the secondary neutron field leaking from 18O enriched H2O target in IBA Cyclone 18/9. Experimental characterization is based on the employment of independent methods, namely the proton recoil method using a stilbene scintillation detector and neutron activation analysis with selected IRDFF materials. Neutron field characteristics were also tested by calculation in the standard MCNP6 code model and using FENDL-3, TENDL-2017 nuclear data libraries for (p,n) reactions. The calculation models have been found as discrepant in some quantities more or less, thus it is recommended to use experimental characterization as a sole method.

Activation studies of a PET cyclotron bunker

During the operational life of a PET Cyclotron, the concrete walls of its vault are activated by secondary neutrons. For this reason when considering dismantling of such accelerators, a considerable amount of low level solid radioactive waste has to be characterized and disposed. To decrease future dismantling costs, the amount of radioactive waste has to be evaluated in advance to define an optimum decommissioning strategy. Aim of this work is to develop methodologies for the preliminary assessment of activation induced in a bunker via experimental measurements. Two different facilities were studied and different approaches were adopted: non-destructive, in field measurements using a portable CZT detector were performed in the bunker of a 16.5 MeV GE PETtrace (S. Orsola-Malpighi Hospital of Bologna); while core drilling samples were extracted from the bunker of an 18 MeV IBA Cyclone 18 H C (Inselspital in Bern) and measured in laboratory with an HPGe detector. The principal long-lived radionuclides found in concrete were Eu-152, Mn-54, Co-60, Sc-46, Cs-134 with activity concentrations comprised between 0.01 and 0.6 Bq/g. In all performed measurements the total activity concentration exceed the clearance level of Directive (2013)/59/Euratom. Considering a hypothetical decommissiong of the two facilities, the amount of low lever radioactive waste estimated was about 93 m3 in the case of S. Orsola-Malpighi, while about 58 m3 for Insespital facility. Both the methodologies have proved to be adequate for the purposes.

Measurement of the Beam Energy Distribution of a Medical Cyclotron with a Multi-Leaf Faraday Cup

Accurate knowledge of the beam energy distribution is crucial for particle accelerators, compact medical cyclotrons for the production of radioisotopes in particular. For this purpose, a compact instrument was developed, based on a multi-leaf Faraday cup made of thin aluminum foils interleaved with plastic absorbers. The protons stopping in the aluminum foils produce a measurable current that is used to determine the range distribution of the proton beam. On the basis of the proton range distribution, the beam energy distribution is assessed by means of stopping-power Monte Carlo simulations. In this paper, we report on the design, construction, and testing of this apparatus, as well as on the first measurements performed with the IBA Cyclone 18-MeV medical cyclotron in operation at the Bern University Hospital.

Measurement of the proton beam energy of a medical cyclotron based on Rutherford Back-scattering Analysis

For the first time the Rutherford Back-Scattering Spectroscopy (RBS) technique has been successfully exploited for the measurement of the energy of a proton beam accelerated by the IBA Cyclone 18/18 medical cyclotron in operation at the Bern University Hospital. This accelerator, routinely used for radioisotope production for Positron Emission Tomography (PET) imaging is equipped with an external beam line devoted to research activities in several fields such as detector physics, medical applications of particle physics, accelerator physics. Recently a widespread request has raised for the availability of well characterized proton and neutron beams, particularly for radiation hardness studies and the development of new neutron detectors. A feasibility study for a future upgrade of the Bern cyclotron towards a neutron facility was started, which requires a complete and precise characterization of the proton beam. Along this line, the measurement of fundamental parameters of the primary proton beam, such as the maximum proton energy and its spread have been performed by means of the RBS technique with two different targets, namely gold and graphite foils.

LONG-LIVED RADIONUCLIDES IN THE PRODUCTION OF [18F]FLUOROCHOLINE FOR PET-DIAGNOSIS

In the present study the distribution of long-lived radionuclides between the drug product, recovered water [ 18O]H2 O and solid phase extraction cartridges was studied in [18F]fluorocholine production process. Isotopic composition for long-lived nuclides (half-lives = 10–312 days) was determined, the mechanisms of their formation and accumulation on cartridges are considered. It was shown that in the batches of pharmaceutical produced the content of long-lived nuclides is by 5 orders of magnitude lower than the limit value specified by the appropriate 07/2016:2793 European Pharmacopoeia article. The results obtained are of vital importance for optimization of the procedures for radioactive waste management in the production of [18F]fluorocholine using IBA Cyclone 18/9 HC cyclotron and, consequently, for minimization of radiation exposure of personnel.

A system for online beam emittance measurements and proton beam characterization

A system for online measurement of the transverse beam emittance was developed. It is named 4PrOBεaM (4-Profiler Online Beam Emittance Measurement) and was conceived to measure the emittance in a fast and efficient way using the multiple beam profiler method. The core of the system is constituted by four consecutive UniBEaM profilers, which are based on silica fibers passing across the beam. The 4PrOBεaM system was deployed for characterization studies of the 18 MeV proton beam produced by the IBA Cyclone 18 MeV cyclotron at Bern University Hospital (Inselspital). The machine serves daily radioisotope production and multi-disciplinary research, which is carried out with a specifically conceived Beam Transport Line (BTL). The transverse RMS beam emittance of the cyclotron was measured as a function of several machine parameters, such as the magnetic field, RF peak voltage, and azimuthal angle of the stripper. The beam emittance was also measured using the method based on the quadrupole strength variation. The results obtained with both techniques were compared and a good agreement was found. In order to characterize the longitudinal dynamics, the proton energy distribution was measured. For this purpose, a method was developed based on aluminum absorbers of different thicknesses, a UniBEaM detector, and a Faraday cup. The results were an input for a simulation of the BTL developed in the MAD-X software. This tool allows machine parameters to be tuned online and the beam characteristics to be optimized for specific applications.