64Cu Reaction Research Articles

Production of 67Cu at a biomedical cyclotron via 70Zn(p,α)67Cu reaction and its evaluation in a preclinical study using small animal SPECT/CT

Clinical advancements in nuclear medicine theranostics has excited a research interest in exploring novel radionuclides for medical use. The duo of the β- emitter 67Cu and the positron emitter 64Cu, has advantages over the well-established clinical pair 68Ga and 177Lu in terms of capability for high-precision therapy. Low availability has hindered the use of 67Cu whereas 64Cu has become established at a limited number of sites through production in low-to-medium energy biomedical cyclotrons. Via the reaction 70Zn(p,α)67Cu, 67Cu can also be cyclotron produced, although data on the cross sections of this reaction are sparse. Our aim in this study was three-fold: 1) to establish cross sections for relevant beam energies (14-16 MeV) of the 70Zn(p,α)67Cu reaction; 2) determine experimentally the thick target yield for 16.5 MeV proton beam; 3) establish a routine production of 67Cu for radiochemical and preclinical research. Additionally, our work aims to explore the feasibility of using biomedical cyclotrons for developing of novel therapeutic radionuclides.Thin layers of enriched 70Zn were electrodeposited onto silver foils to employ the stacked foils technique for assessing the cross section at six energies. The thick target yield was measured experimentally using a pressed [70Zn]ZnO target. Methods were developed for solid phase extraction separation of 67Cu from the target material, as well as quality control of the product with regards to radionuclidic and radiochemical purity. Radiolabelling of PSMA-617 precursor was performed and the end product injected in a healthy mouse for a kinetic study. As a proof of concept for preclinical applications The animal was then SPECT imaged using the 185 keV gamma emission line.Summarizing, our data confirm that biomedical cyclotrons can contribute in developing novel radionuclides, even of low cross section, for preclinical research.

Nuclear model calculation of yield for 64Cu radionuclide produced in 65Cu(α, x)64Cu reaction at ≈ 10–40 MeV

This paper used theoretical nuclear model calculations to estimate the production yield of medically important 64Cu radionuclide produced in the interaction of α-projectile with 65Cu-target at ≈10–40 MeV. Production cross-sections were predicted using TALYS-1.9(G), EMPIRE 3.2, and ALICE/ASH reaction model codes. Generally, the TALYS-1.95(G) predicted and measured cross-sections to produce 64Cu radionuclide are in very good agreement. Further, the statistical analysis of Pearson's coefficient confirmed strong positive correlations between TALYS-1.95(G) predictions and most experimentally measured production cross-sections. The calculated thick target yields of 64Cu radionuclide showed that 65Cu(α, x)64Cu reaction resulted in a maximum yield of up to ≈ 1423 MBq/μAh at ≈ 30 MeV. Furthermore, analyzes of isotopic impurities produced during 64Cu production could only give rise to the significant yield of 66Cu impurity as much as ≈ 1988 MBq/μAh, which complicated the process of radiochemistry; however, the relatively short half-life of 66Cu isotopic impurity could only demand a waiting time of about 1.5 h to decrease its contribution to a negligible level.The yield obtained for the 64Cu radionuclide via the 65Cu(α, x)64Cu route is significant. It validates the viability of this production route and underscores its potential as a promising option for the optimized supply of 64Cu in radiopharmaceutical applications. While further investigations on quality validating parameters are necessary, the potential of the 65Cu(α, x)64Cu production route cannot be overstated.

The spectrum-averaged cross section investigation of 117Sn(n,n')117mSn and 67Zn(n,p)67Cu reactions

The spectrum averaged cross sections (SACS) in standard neutron field, e.g. 252Cf(s.f.), is a preferable tool for cross section evaluation and validation. A set of reaction measurements with high energy thresholds was previously performed. The presented work focuses on lower energy threshold reactions, namely on the inelastic scattering of the tin foil, more specifically the reaction 117Sn(n,n')117mSn, and the zinc foil reaction, namely 67Zn(n,p)67Cu. These reactions are of special interest due to their intermediate energy range, which is essential in classical reactor dosimetry and fast reactor dosimetry. The experiments were carried out in a standard neutron field formed by 252Cf(s.f.) source in Řež. The experimental results were compared with calculations using MCNP6.2, ENDF/B-VII.1 transport library, and ENDF/B-VIII.0 and IRDFF-II cross section data library. Additionally, the calculations using CEA code DARWIN/PEPIN2 using JEFF-3.0/A were executed. The obtained experimental SACS of previously measured reactions were in good agreement with the SACS calculated using the IRDFF-II library. Additionally, the calculational reaction rate of 67Zn(n,p)67Cu was in accordance with the experimental data in case of ENDF/B-VIII.0 nuclear data library. Moreover, the calculational results of 117Sn(n,n')117mSn obtained by DARWIN/PEPIN2 code (using JEFF-3.0/A nuclear data library) are closest to the experimental results.

Cross-Section Calculations of Medical Radioisotope 64Cu via some Proton, Neutron and Deuteron Reactions

The Copper-64 radioisotope, whose academic research continues on diagnostic and therapeutic use, was examined in this study. 64Cu radioisotope is unique among other Cu isotopes for medical usage due to its low positron energy, appropriate half-life, and short tissue penetration. In cases where experimental data are missing, cross-section calculations can be used, and the existence of the cross-section data may provide various advantages in managing time, cost, and efficiency. In this context, investigated detailed cross-section calculations of the 64Cu isotope. To this end, cross-sections acquired from various calculation codes were compared with the literature, and alternative production routes were investigated. Using the nuclear reaction codes TALYS and EMPIRE, cross-section data of the 64Cu isotope were obtained from the 64Ni(p,n)64Cu, 65Cu(p,n+p)64Cu, 68Zn(p,n+α)64Cu, 65Cu(n,2n)64Cu, 64Ni(d,2n)64Cu, and 63Cu(d,p)64Cu reactions with the equilibrium and pre-equilibrium models. The results were compared with the available literature data from the EXFOR database.

Monte Carlo simulation of 64Cu production

Cooper-64 (64Cu) has good potential for use in the diagnosis and treatment of tumors. It can be produced by irradiating an enriched 64Ni target with a small proton cyclotron system. Based on the demand for 64Cu, a suitable production plan can be developed. Due to the high cost of 64Ni, it is important to simulate the production process in order to find a cost-effective method for producing 64Cu. In this work, Geant4 software was used in conjunction with the Evaluated Nuclear Data File (ENDF/B-VII.1) and the TALYS-based Evaluated Nuclear Data Library (TENDL-2019) to calculate the 64Ni(p,n)64Cu reaction cross section. The TRIM code was then used to calculate the proton projection range in the 64Ni target. Finally, the saturation yield of 64Cu was obtained for proton energies between 2 MeV and 20 MeV and target thicknesses ranging from 0.1 mm to 1 mm.

Biochemical separation of Cetuximab-Fab from papain-digested antibody fragments and radiolabeling with 64Cu for potential use in radioimmunotheranostics

Engineered Fab fragments of monoclonal antibodies (mAbs) after radiolabeling with suitable radiometals have the potential to play a key role in personalized radioimmunotheranostics of cancer patients. In this study, we have generated Fab fragment of Cetuximab, a mAb targeting epidermal growth factor receptor (EGFR) expression and purified from the Fc and other fragments by ultrafiltration and affinity chromatography. The Cetuximab-Fab was conjugated with a suitable bifunctional chelator and radiolabeled with no-carrier-added (NCA) 64Cu produced via 64Zn (n, p) 64Cu reaction in a nuclear reactor. The radioimmunoconjugate obtained after size exclusion chromatographic separation possessed >95% radiochemical purity and it retained its integrity over at least three half-lives of the radiometal. Biodistribution studies was performed in fibrosarcoma tumor bearing Swiss mice, which demonstrated the explicit need for purification of the Cetuximab-Fab from Fc fragments. Enhanced and rapid tumor uptake with decent tumor-to-background ratio with prolonged retention was observed when radiolabeled purified Cetuximab-Fab was intravenously administered in animal models. Overall, this preclinical study established the pivotal role of separation science and technology to obtain the radioimmunoconjugate with requisite purity in order to demonstrate optimal pharmacokinetics and maximized treatment efficacy.

Cyclotron-Based Production of 67Cu for Radionuclide Theranostics via the 70Zn(p,α)67Cu Reaction.

Theranostic matched pairs of radionuclides have aroused interest during the last couple of years, and in that sense, copper is one element that has a lot to offer, and although 61Cu and 64Cu are slowly being established as diagnostic radionuclides for PET, the availability of the therapeutic counterpart 67Cu plays a key role for further radiopharmaceutical development in the future. Until now, the 67Cu shortage has not been solved; however, different production routes are being explored. This project aims at the production of no-carrier-added 67Cu with high radionuclidic purity with a medical 30MeV compact cyclotron via the 70Zn(p,α)67Cu reaction. With this purpose, proton irradiation of electrodeposited 70Zn targets was performed followed by two-step radiochemical separation based on solid-phase extraction. Activities of up to 600MBq 67Cu at end of bombardment, with radionuclidic purities over 99.5% and apparent molar activities of up to 80MBq/nmol, were quantified.

Microfluidic solvent extraction of no-carrier-added 64Cu from irradiated Zn target for radiopharmaceutical preparation

Microfluidics based liquid-liquid extraction is emerging as an enabling and powerful technology in radiochemical separations of medically important radioisotopes. In this study, we report the production of high specific activity 64Cu via 64Zn (n, p) 64Cu reaction in a research reactor. A microfluidic continuous flow liquid-liquid extraction system based on the use of dithizone as extractant was developed for efficient separation of miniscule quantity of 64Cu (in ng level) from bulk irradiated Zn target (in g level). The extraction process is completely selective for 64Cu, which could subsequently be retrieved in the desired medium for preparation of radiopharmaceuticals. The overall yield of 64Cu after the separation process was > 85 % and it was obtained with adequately high radionuclidic, radiochemical and chemical purities. Additionally, the effective specific activity of radio chemically separated 64Cu was determined to be 12.2 ± 0.8 GBq/µg, which is quite close to that reported for cyclotron produced no-carrier-added (NCA) 64Cu available commercially. The final 64Cu formulation could be effectively used for preparation of a variety of radiopharmaceuticals with high radiolabeling yields. The promising results obtained in this study open the pathway to achieve continuous and efficient recovery of reactor produced NCA 64Cu from the irradiated target using an automated microfluidic setup.

Cyclotron production of 64Cu by proton irradiation of enriched 64Ni target: Validation of Geant4 simulation parameters through experimental data

The use of radioisotopes in nuclear medicine applications became essential for the diagnosis and follow-up imaging of many oncological, cardiovascular, and neurodegenerative diseases, in a safe and non-invasive way. Their use in the personalized treatment of tumors is on the verge to change the oncological patient management. Optimization of the radioisotopes production aims to maximize the production efficiency while minimizing side reactions and costs. A practical approach to balance these non-converging ways is to employ the simulation tools in the process design phase and experimental setup. In this way, the production yield can be estimated and the radionuclide impurities content that appears during the bombardment of the target of interest can be optimally set below acceptable limits. Copper-64 is an emerging radionuclide in nuclear medicine theragnostic applications due to three decay modes, namely electron capture, electron (β−) and positron (β+) emissions, and a 12.7 h half-life, favorable for visualization of fast biological processes. Optimization of 64Cu production by irradiation of enriched 64Ni targets with protons in a particular geometry on a TR-19 cyclotron is discussed in this work. The simulated activity produced on different levels of enrichment of the 64Ni targets was calculated using the Monte Carlo simulation in the Geant4 platform, where a customized solid target irradiation system set-up was replicated; the obtained parameters were implemented in the experiments and the results were compared, aiming to validate the simulation parameters through experimental data.As the simulated and experimental results regarding the production of 64Cu via64Ni(p,n)64Cu reaction are in good compliance, the tool can be further applied for the optimization of the production of other radionuclides on the same set-up.

A digital twin for 64Cu production with cyclotron and solid target system

One method for finding reliable and cost-effective solutions for designing radioisotope production systems is represented by the “digital twin” philosophy of design. Looking at cyclotron solid targets, uncertainties of the particle beam, material composition and geometry play a crucial role in determining the results. The difference between what has been designed and what can be effectively manufactured, where processes such as electroplating are poorly controllable and generate large non-uniformities in deposition, must also be considered. A digital twin, where the target geometry is 3D scanned from real models, can represent a good compromise for connecting “ideal” and “real” worlds. Looking at the 64Ni(p,n)64Cu reaction, different Unstructured-Mesh MCNP6 models have been built starting from the 3D solid target system designed and put into operation by COMECER. A characterization has been performed considering the designed ideal target and a 3D scan of a real manufactured target measured with a ZEISS contact probe. Libraries and physics models have been also tested due to limited cross-section data. Proton spectra in the target volume, 3D proton-neutron-photon flux maps, average energies, power to be dissipated, shut-down dose-rate, 64Cu yield compared with various sources of experimental data and beam axial shifting impact, have been estimated. A digital twin of the 64Ni(p,n)64Cu production device has been characterized, considering the real measured target geometry, paving the way for a fully integrated model suitable also for thermal, structural or fluid-dynamic analyses.

Excitation functions for fast-neutron induced reactions on zinc

Cross sections of the 64Zn(n, p)64Cu, natZn(n, x)67Cu, 66Zn(n, 2n)65Zn and 70Zn(n, 2n)69mZn reactions have been measured by using the activation technique at 14.0 MeV neutron energy. The neutrons were produced via the 3H(d, n)4He reaction. The present experimental data illustrated satisfactory agreement with most of the previously reported experimental data. Experimental data are compared with evaluated nuclear data of the CENDL-3.2, ENDF/B-VIII.0, JENDL-5, BROND-3.1 and JEFF-3.3 libraries. Besides, these excitation functions were calculated by using theoretical model of the TALYS-1.96 code from thresholds up to 20 MeV. A group set of parameters was obtained which better reproduce the experimental data than the default parameters.

Alternative routes for 64Cu production using an 18 MeV medical cyclotron in view of theranostic applications

Radiometals play a fundamental role in the development of personalized nuclear medicine. In particular, copper radioisotopes are attracting increasing interest since they offer a varying range of decay modes and half-lives and can be used for imaging (60Cu, 61Cu, 62Cu and 64Cu) and targeted radionuclide therapy (64Cu and 67Cu), providing two of the most promising true theranostic pairs, namely 61Cu/67Cu and 64Cu/67Cu. Currently, the most widely used in clinical applications is 64Cu, which has a unique decay scheme featuring β+-, β−-decay and electron capture. These characteristics allow its exploitation in both diagnostic and therapeutic fields. However, although 64Cu has extensively been investigated in academic research and preclinical settings, it is still scarcely used in routine clinical practice due to its insufficient availability at an affordable price. In fact, the most commonly used production method involves proton irradiation of enriched 64Ni, which has a very low isotopic abundance and is therefore extremely expensive. In this paper, we report on the study of two alternative production routes, namely the 65Cu(p,pn)64Cu and 67Zn(p, α)64Cu reactions, which enable low and high 64Cu specific activities, respectively. To optimize the 64Cu production, while minimizing the mass of copper used as a target in the first case, or the co-production of other copper radioisotopes in the second case, an accurate knowledge of the production cross sections is of paramount importance. For this reason, the involved nuclear reaction cross sections were measured at the Bern medical cyclotron laboratory by irradiating enriched 65CuO and enriched 67ZnO targets. On the basis of the obtained results, the production yield and purity were calculated to assess the optimal irradiation conditions. Several production tests were performed to confirm these findings.

An overview of activation cross-section measurements of some neutron and charged-particle induced reactions in Bangladesh

Abstract Over the last several decades, our research group has been working on nuclear data measurements using a J-25 Neutron Generator, a TRIGA Mark II Research Reactor and a Tandem Accelerator at Savar, as well as an Am/Be neutron source at Rajshahi. The spectrum of fast neutrons having energies from 0.5 to 20 MeV in the core of the TRIGA reactor as well as from 1.5 to 11 MeV of the Am/Be source was well characterized for validation of evaluated data of neutron threshold reactions. Spectrum-averaged cross sections were determined by integral measurements. The integral values measured at both the reactor and the Am/Be source were compared with the integrated data deduced from measured and evaluated excitation functions of some nuclear reactions given in some data libraries. As example, the details on the integral and integrated cross sections of the 64Zn(n,p)64Cu and 60Ni(n,p)60Co reactions are discussed. In both cases, integral test shows that further improvement of the evaluated excitation function reported in data libraries is needed. The use of a newly developed facility at the 3 MV Tandem Accelerator in measurement of proton induced reaction cross sections in the energy region below 5 MeV is outlined, and new results on the 64Ni(p,n)64Cu and natNi(p,x)61Cu processes below 3 MeV are discussed.

Validation of the neutron lead transport for fusion applications

Lead is an important material, both for fusion or fission reactors. The cross sections of natural lead should be validated because lead is a main component of lithium-lead modules suggested for fusion power plants and it directly affects the crucial variable, tritium breeding ratio. The presented study discusses a validation of the lead transport libraries by dint of the activation of carefully selected activation samples. The high emission standard 252Cf neutron source was used as a neutron source for the presented validation experiment. In the irradiation setup, the samples were placed behind 5 and 10 cm of the lead material. Samples were measured using a gamma spectrometry to infer the reaction rate and compared with MCNP6 calculations using ENDF/B-VIII.0 lead cross sections. The experiment used validated IRDFF-II dosimetric reactions to validate lead cross sections, namely 197Au(n, 2n)196Au, 58Ni(n,p)58Co, 93Nb(n, 2n)92mNb, 115In(n,n')115mIn, 115In(n,γ)116mIn, 197Au(n,γ)198Au and 63Cu(n,γ)64Cu reactions. The threshold reactions agree reasonably with calculations; however, the experimental data suggests a higher thermal neutron flux behind lead bricks. The paper also suggests 252Cf isotropic source as a valuable tool for validation of some cross-sections important for fusion applications, i.e. reactions on structural materials, e.g. Cu, Pb, etc.

Evaluation of production cross-sections for theranostic 67Cu radionuclide via proton-induced nuclear reaction on 68Zn target

Copper-67 (T1/2 = 61.83 h, Eβ−mean=141 keV, Iβ−total=100%; Eγ = 184.577 keV, Iγ = 48.7%) is a promising radionuclide for theranostic applications especially in radio immunotherapy. However, one of the main drawbacks for its application is related to its limited availability. Various nuclear reaction routes investigated in the last years can result in 67Cu production, although the use of proton beams is the method of choice taken into account in this work. The goal of this work is a revision of the cross-sections aimed at 67Cu yield, which were evaluated for the 68Zn(p,2p)67Cu reaction route up to 80 MeV proton energy. A well-defined statistical procedure, i.e., the Simultaneous Evaluation on KALMAN (SOK), combined with the least-squares concept, was used to obtain the evaluated data together with the covariance matrix. The obtained evaluated data were also compared to predictions provided by the nuclear reaction model codes TALYS and EMPIRE, and a partial agreement among them has been found. These data may be useful for both existing and potential applications in nuclear medicine, to achieve an improvement and validation of the various nuclear reaction models, and may also find applications in other fields (e.g., activation analysis and thin layer activation).

Precision measurement of relative [formula omitted]-ray intensities from the decay of 61Cu

A discrepancy, well outside reported uncertainties, has been observed between the accepted and measured values of the intensity ratio of the two strongest γ rays following 61Cu β+ decay. This discrepancy has significant impact since the natNi(d,x)61Cu reaction has historically been one of only a few IAEA recommendations for use as a deuteron flux monitor and a considerable number of published cross sections measured in ratio to that beam monitor cross section may depend on the choice of either the first or second strongest γ ray in those calculations. To determine the magnitude of this error most precisely, over a hundred separate measurements of the 283 keV to 656 keV γ-ray emission ratio were collected from seven experiments and a variety of detectors and detection geometries. A weighted average of all these measurements indicates an error in the value listed in the Nuclear Data Sheets of 11% in either the primary or second-highest intensity γ ray of 61Cu, potentially introducing an 11% error in 61Cu production cross section measurements, cross sections using nickel activation as a deuteron beam current monitor, or in dose rates when 61Cu is used in nuclear medicine. General agreement with the Data Sheets with ten other intensity ratios suggests the most probable error is in the secondary (656 keV) emission, which accordingly should be updated from 10.8% to 9.69%.

Methodology of 63Cu(n,2n)62Cu Reaction Rate Measurement

Abstract This paper presents the measurement of the spectrum-averaged cross section (SACS) of 63Cu(n,2n)62Cu reaction in 252Cf spontaneous fission neutron spectrum. The SACS in the 252Cf spectrum was chosen as a validation tool since 252Cf is the only standard neutron field and 62Cu isotope is not easy to measure by gamma spectroscopy since the gamma line of interest is an annihilation peak, which is also produced by 64Cu isotope. Fortunately, contributions to the annihilation peak from these isotopes can be distinguished due to the very different half-lives. SACS was inferred from the experimental reaction rate. The SACS in the 252Cf spontaneous fission neutron field for the 63Cu(n,2n)62Cu reaction was determined as equal to (0.1763 ± 0.0077 mb). This value agrees with value (0.183 ± 0.007) × 10−3 b within uncertainty presented by W. Mannhart. However, it differs by 12.7% from IRDFF-II value, which is equal to (0.19874 ± 8.954 10−3) × 10−3 b. Furthermore, reasonable agreement is not achieved with ENDF/B-VIII.0, JEFF-3.3, CENDL-3.1, ROSFOND-2010, nor JENDL-4.0 nuclear data libraries.

Reactor produced [64Cu]CuCl2 as a PET radiopharmaceutical for cancer imaging: from radiochemistry laboratory to nuclear medicine clinic

Copper-64 is a useful theranostic radioisotope that is attracting renewed interest from the nuclear medicine community in the recent times. This study aims to demonstrate the utility of research reactors to produce clinical-grade 64Cu via 63Cu(n,γ)64Cu reaction and use it in the form of [64Cu]CuCl2 as a radiopharmaceutical for PET imaging of cancer in human patients. Copper-64 was produced by irradiation of natural CuO target in a medium flux research reactor. The irradiated target was radiochemically processed and detailed quality control analyses were carried out. Sub-acute toxicity studies were carried out with different doses of Cu in Wistar rats. The biological efficacy of the radiopharmaceutical was established in preclinical setting by biodistribution studies in melanoma tumor bearing mice. After getting regulatory approvals, [64Cu]CuCl2 formulation was clinically used for PET imaging of prostate cancer and glioblastoma patients. Large-scale (~ 30GBq) production of 64Cu could be achieved in a typical batch and it was adequate for formulation of clinical doses for multiple patients. The radiopharmaceutical met all the purity requirements for administration in human subjects. Studies carried out in animal model showed that the toxicity due to "cold" Cu in clinical dose of [64Cu]CuCl2 for PET scans would be negligible. Clinical PET scans showed satisfactory uptake of the radiopharmaceutical in the primary cancer and its metastatic sites. To the best of our knowledge, this is the first study on use of reactor produced [64Cu]CuCl2 for PET imaging of cancer in human patients. It is envisaged that this route of production of 64Cu would aid towards affordable availability of this radioisotope for widespread clinical use in countries with limited cyclotron facilities.

A simple and robust method for radiochemical separation of no-carrier-added 64Cu produced in a research reactor for radiopharmaceutical preparation

Copper-64 is an excellent theranostic radiometal that is gaining renewed attention of the clinical community in the recent times. In order to meet the increasing demand of this radiometal, we have demonstrated the viability of its production via 64Zn (n,p) 64Cu reaction in a nuclear reactor. A semi-automated radiochemical separation module based on selective extraction of 64Cu as dithizonate complex was developed. The maximum available activity at the end of irradiation was ~ 700 MBq. The overall yield of 64Cu after the separation process was >85% and it could be obtained with ~12 GBq/μg specific activity, >99.9% radionuclidic purity and >98% radiochemical purity. The separated 64Cu could be utilized for preparation of a wide variety of radiopharmaceuticals.

Production Cross–Section Calculations of 62Cu via Charged Particles Induced Reactions

The utilization of radioisotopes has been increasing proportionally with the scientific and industrial developments. Among many known and used examples of them, 62Cu has a wide usage due to its suitability for many specific requirements such as in medical applications. By considering the importance of radioisotopes and especially 62Cu, in this study, the theoretical calculations of cross–section values for 62Cu via 59Co(α,n)62Cu, 61Ni(d,n)62Cu, 62Ni(d,2n)62Cu and 62Ni(p,n)62Cu reactions were carried out by employing three phenomenological level density models via TALYS 1.9 code. Obtained results were compared with the available experimental data from Experimental Nuclear Reaction Data (EXFOR) Library by graphically and mathematically.