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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.

The present work promotes and validates the benefits of using niobium instead of Havar® as the material for the target windows in most routine irradiations in cyclotrons. Calculation of the material activation and measurements of the contamination of the transferred target liquids show major improvements with the use of niobium. Also, the data of the daily routine productions at our production center are presented, proving that Havar® is not mandatory unless large target currents and/or pressures are required.

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.

Abstract Over the last several years, the use of radiometals has gained increasing relevance in supporting the continuous development of new, complementary and more specific biological targeting agents. Radiopharmaceuticals labelled with radiometals from elements such as Tc, Zr, Y, Ga and Cu received increasing attention as they find application in both diagnostic SPECT and PET imaging techniques and radiotherapeutic purposes. Such interest stems from the wide variety of radionuclides available with distinct and complementary nuclear decay characteristics to choose from with unequalled specificity, but can also be explained by growing demand in targeted radionuclide therapy. As a result, as routine supply of these radiometals becomes mandatory, studies describing their production processes have expanded rapidly. Although most radiometals are traditionally provided by the irradiation of solid targets in specialized cyclotrons, recently developed techniques for producing radiometals through the irradiation of liquid targets have received growing attention due to compatibility with commonly available small medical cyclotrons, promising characteristics and encouraging results. Irradiating liquid targets to produce radiometals appears as a fast, reliable, convenient and cost-efficient alternative to the conventional solid target techniques, characterized by complex and time-consuming pre- and post-irradiation target handling. Production of radiometals in liquid targets incorporated to complete manufacturing processes for daily routine is already recognized as a viable alternative and complementary supply methodology to existing solid target based infrastructures to satisfy growing clinical demands. For instance, several sites already use the approach to produce 68Ga-radiopharmaceuticals for clinical use. This review article covers the production of common radiometals with clinical potential through the irradiation liquid targets. A comparison with the traditional solid target irradiation methods is presented when relevant.

The present work describes a method to determine excitation function curves and, therefore, cross-sections, making use of the irradiation of liquid targets at distinct energies in a biomedical cyclotron. The method relies on the derivative of experimentally measured thick target yield curves to determine the corresponding excitation function curves. The technique is presented as a valid and practical alternative to the commonly used activation method combined with the stack monitor technique, whose implementation in liquid targets offers practical difficulties. The working principle is exemplified by presenting the results obtained for the clinically relevant 68Zn(p,n)68Ga and the 64Zn(p,α)61Cu nuclear reactions, obtained though the irradiation of liquid targets containing dissolved natural zinc.

This work presents a simulation model developed with the aim to represent and study the thermal behavior of cyclotron liquid targets. Understanding and improving the thermal behavior of the target system is fundamental to improving the target overall performance, especially when using thick target windows, for which a larger amount of heat generated can be limiting. ANSYS CFX and SRIM software were used to develop a simulation model representing the IBA Nirta® Ga-68 liquid target system, to study the use of thick niobium target windows. The model was validated by comparing the results with experimental data obtained for the same liquid target system. In the present study, simulation results and temperature distributions of the main target components were obtained by studying the main parameters of interests, such as the initial temperature and mass flow rate of the coolants, and also distinct target windows with different thicknesses.

The present work describes an experimental system enabling temperature measurement in cyclotron targets’ cooling water during bombardment. The developed system provides sensible and immediate response to variations of irradiation conditions during bombardment and enables quantification of the temperature rise in the cooling water due to beam interaction with the irradiated target and with its collimator. Such a system finds application either as a monitoring safety device to instantaneously detect and register abnormal alterations in target conditions to anticipate thermal-related incidents and as a tool to experimentally validate cyclotron targetry optimization studies and thermal simulations.

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.

PET imaging has gained significant momentum in the last few years, especially in the area of oncology, with an increasing focus on metal radioisotopes owing to their versatile chemistry and favourable physical properties. Copper-61 (t1/2 = 3.33 h, 61% β+, Emax = 1.216 MeV) provides unique advantages versus the current clinical standard (i.e., gallium-68) even though, until now, no clinical amounts of 61Cu-based radiopharmaceuticals, other than thiosemicarbazone-based molecules, have been produced. This study aimed to establish a routine production, using a standard medical cyclotron, for a series of widely used somatostatin analogues, currently labelled with gallium-68, that could benefit from the improved characteristics of copper-61. We describe two possible routes to produce the radiopharmaceutical precursor, either from natural zinc or enriched zinc-64 liquid targets and further synthesis of [61Cu]Cu-DOTA-NOC, [61Cu]Cu-DOTA-TOC and [61Cu]Cu-DOTA-TATE with a fully automated GMP-compliant process. The production from enriched targets leads to twice the amount of activity (3.28 ± 0.41 GBq vs. 1.84 ± 0.24 GBq at EOB) and higher radionuclidic purity (99.97% vs. 98.49% at EOB). Our results demonstrate, for the first time, that clinical doses of 61Cu-based radiopharmaceuticals can easily be obtained in centres with a typical biomedical cyclotron optimised to produce 18F-based radiopharmaceuticals.

An automated process for the production and purification of radiometals produced by irradiating liquid targets in a medical cyclotron, using a commercially available module, has been developed. The method is suitable for the production and purification of radiometals such as 68Ga, 64Cu and 61Cu through irradiation of liquid targets and is important for producing high specific activity radioisotopes with a substantial reduction in processing time and cost when compared with the solid target approach. The “liquid target” process also eliminates the need for pre- and post-irradiation target preparation and simplifies the transfer of irradiated material from target to hotcell. A 68GaCl3 solution can be obtained in about 35 min with an average yield of 73.9 ± 6.7% in less than 10 mL of volume. 64CuCl2 solutions can be obtained with an average yield of 81.2 ± 7.8% in about 1 h of processing time. A dedicated single-use disposable kit is used on a commercial IBA Synthera® extension module.