Production Of 64Cu Research Articles

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.

64Cu production via the 68Zn(p,nα)64Cu nuclear reaction: An untapped, cost-effective and high energy production route

IntroductionCopper-64 (64Cu, t1/2 = 12.7 h) is a positron emitter well suited for theranostic applications with beta-emitting 67Cu for targeted molecular imaging and radionuclide therapy. The present work aims to evaluate the radionuclidic purity and radiochemistry of 64Cu produced via the 68Zn(p,nα)64Cu nuclear reaction. Macrocyclic chelators DOTA, NOTA, TETA, and prostate-specific membrane antigen ligand PSMA I&T were radiolabeled with purified 64Cu and tested for in vitro stability. [64Cu]Cu-PSMA I&T was used to demonstrate in vivo PET imaging using 64Cu synthesized via the 68Zn(p,nα)64Cu production route and its suitability as a theranostic imaging partner alongside 67Cu therapy. Methods64Cu was produced on a 24 MeV TR-24 cyclotron at a beam energy of 23.5 MeV and currents up to 70 μA using 200 mg 68Zn encapsulated within an aluminum‑indium-graphite sealed solid target assembly. 64Cu semi-automated purification was performed using a NEPTIS Mosaic-LC synthesis unit employing CU, TBP, and TK201 (TrisKem) resins. Radionuclidic purity was measured by HPGe gamma spectroscopy, while ICP-OES assessed elemental purity. Radiolabeling was performed with NOTA at room temperature and DOTA, TETA, and PSMA I&T at 95 °C. 64Cu incorporation was studied by radio-TLC. 64Cu in vitro stability of [64Cu]Cu-NOTA, [64Cu]Cu-DOTA, [64Cu]Cu-TETA, and [64Cu]Cu-PSMA I&T was assessed at 37 °C from 0 to 72 h in human blood serum. Preclinical PET imaging was performed at 1, 24, and 48 h post-injection with [64Cu]Cu-PSMA I&T in LNCaP tumor-bearing mice and compared with [68Ga]Ga-PSMA I&T. ResultsMaximum purified activity of 4.9 GBq [64Cu]CuCl2 was obtained in 5 mL of pH 2–3 solution, with 2.9 GBq 64Cu concentrated in 0.5 mL. HPGe gamma spectroscopy of purified 64Cu detected <0.3 % co-produced 67Cu at EOB with no other radionuclidic impurities. ICP-OES elemental analysis determined <1 ppm Al, Zn, In, Fe, and Cu in the [64Cu]CuCl2 product. NOTA, DOTA, TETA, and PSMA I&T were radiolabeled with 64Cu, resulting in maximum molar activities of 164 ± 6 GBq/μmol, 155 ± 31 GBq/μmol, 266 ± 34 GBq/μmol, and 117 ± 2 GBq/μmol, respectively. PET imaging in PSMA-expressing LNCaP xenografts resulted in high tumor uptake (SUVmean = 1.65 ± 0.1) using [64Cu]Cu-PSMA I&T, while [68Ga]Ga-PSMA I&T yielded an SUVmean of 0.76 ± 0.14 after 60 min post-injection. Conclusions64Cu was purified in a small volume amenable for radiolabeling, with yields suitable for preclinical and clinical application. The 64Cu production and purification process and the favourable PET imaging properties confirm the 68Zn(p,nα)64Cu nuclear reaction as a viable 64Cu production route for facilities with access to a higher energy proton cyclotron, compared to using expensive 64Ni target material and the 64Ni(p,n)64Cu nuclear reaction. Advances in knowledge and implications for patient careOur 64Cu production technique provides an alternative production route with the potential to improve 64Cu availability for preclinical and clinical studies alongside 67Cu therapy.

Proton, neutron and deuteron induced nuclear reactions in medical application

Radioisotopes production is important in medical science as they are used for different purposes. The studies of the nuclear reactions cross-section for the production of 64Cu were performed for the nuclear reactions of 64Ni(p, n)64Cu, 65Cu(p, x)64Cu, 67Zn(p, a)64Cu, 65Cu(n, 2n)64Cu, 64Zn(n, p)64Cu, 64Ni(d, 2n)64Cu, natNi(d,x)64Cu and 66Zn(d, a)64Cu. The calculations were performed using TALYS1.6 nuclear code. The results of excitation functions were compared with experimental data from letratures. It was seen that the results are important to produce copper-64 using different reaction mechanism and thus experimental results and calculations are in good agreement for interesed reactions types.

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.

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.

Cross-section measurement for an optimized 61Cu production at an 18 MeV medical cyclotron from natural Zn and enriched 64Zn solid targets

The availability of novel medical radionuclides is a key point in the development of personalised nuclear medicine. In particular, copper radioisotopes are attracting considerable interest as they can be used to label various molecules of medical interest, such as proteins and peptides, and offer two of the most promising true theranostic pairs, namely 61Cu/67Cu and 64Cu/67Cu. Although 64Cu (t1/2 = 12.7006 h, β+: 17.6%, β−: 38.5%) is nowadays the most commonly used as a diagnostic radionuclide, 61Cu (t1/2 = 3.339 h, β+: 61%) features more favourable nuclear properties, such as a higher positron decay fraction and the absence of β− emissions. To date, the production of 61Cu has been carried out irradiating highly enriched 61Ni targets with a low energy proton beam. However, the use of the very expensive 61Ni targets requires an efficient recovery of the target material and makes this method quite inconvenient. Another promising production route is the proton irradiation of natural Zn or enriched 64Zn targets, exploiting the (p,α) nuclear reaction. Along this line, a research program is ongoing at the Bern medical cyclotron, equipped with an external beam transfer line and a solid target station. In this paper, we report on cross-section measurements of the 64Zn(p,α)61Cu nuclear reaction using natural Zn and enriched 64Zn material, which served as the basis to perform optimized 61Cu production tests with solid targets.

A feasibility study of the therapeutic application of a mixture of 67/64 Cu radioisotopes produced by cyclotrons with proton irradiation.

Purpose 64Cu and 67Cu radioisotopes have nuclear characteristics suitable for nuclear medicine applications. The production of 64Cu is already well established. However, the production of 67Cu in quantities suitable to conduct clinical trials is more challenging as it leads to the coproduction of other Cu isotopes, in particular 64Cu. The aim of this study is to investigate the possibility of using a CuCl2 solution with a mixture of 67/64Cu radioisotopes for therapeutic purposes, providing an alternative solution for the cyclotron production problem.MethodsCopper radioisotopes activities were calculated by considering proton beam irradiation of the following targets: (i) 70Zn in the energy range 70–45 MeV; (ii) 68Zn in the energy range 70–35 MeV; (iii) a combination of 70Zn (70–55 MeV) and 68Zn (55–35 MeV). The contribution of each copper radioisotope to the human‐absorbed dose was estimated with OLINDA/EXM software using the biokinetic model for CuCl2 published by ICRP 53. The total absorbed dose generated by the 67/64CuCl2 mixture, obtained through different production routes, was calculated at different times after the end of the bombardment (EOB). A simple spherical model was used to simulate tumors of different sizes containing uniformly distributed 67/64Cu mixture and to calculate the absorbed dose of self‐irradiation. The biological damage produced by 67Cu and 64Cu was also evaluated through cellular dosimetry and cell surviving fraction assessment using the MIRDcell code, considering two prostate cancer cell lines with different radiosensitivity.ResultsThe absorbed dose to healthy organs and the effective dose (ED) per unit of administered activity of 67CuCl2 are higher than those of 64CuCl2. Absorbed dose values per unit of administered activity of 67/64CuCl2 mixture increase with time after the EOB because the amount of 67Cu in the mixture increases. Survival data showed that the biological damage caused per each decay of 67Cu is greater than that of 64Cu, assuming that radionuclides remain accumulated in the cell cytoplasm. Sphere model calculations demonstrated that 64Cu administered activity must be about five times higher than that of 67Cu to obtain the same absorbed dose for tumor mass between 0.01 and 10 g and about 10 times higher for very small spheres. Consequently, the 64CuCl2‐absorbed dose to healthy organs will reach higher values than those of 67CuCl2. The supplemental activity of the 67/64CuCl2 mixture, required to get the same tumor‐absorbed dose produced by 67CuCl2, triggers a dose increment (DI) in healthy organs. The waiting time post‐EOB necessary to keep this DI below 10% (t 10%) depends on the irradiation methods employed for the production of the 67/64CuCl2 mixture.ConclusionsA mixture of cyclotron produced 67/64Cu radioisotopes proved to be an alternative solution for the therapeutic use of CuCl2 with minimal DI to healthy organs compared with pure 67Cu. Irradiation of a 70Zn+68Zn target in the 70–35 MeV proton energy range for 185 h appears to be the best option from among all the production routes investigated, as it gives the maximum amount of activity, the shortest t 10% (10 h), and less than 1% of 61Cu and 60Cu impurities.

Production of copper-64 using a hospital cyclotron: targetry, purification and quality analysis.

To construct and evaluate a 64Cu production system that minimises the amount of costly 64Ni, radionuclidic impurities and nonradioactive metal contamination and maximises radiochemical and radionuclidic purity and molar activity; and to report analytical and quality control methods that can be used within typical PET radiochemistry production facilities to measure metal ion concentrations and radiometal molar activities. Low volume was ensured by dissolving the irradiated nickel in a low volume of hydrochloric acid (<1 mL) using the concave gold target backing as a reaction vessel in a custom-built target holder. Removal of contaminating 55Co and nonradioactive trace metals was ensured by adding an intermediate hydrochloric acid concentration step during the conventional ion-exchange elution process. The radionuclidic purity of the product was determined by half-life measurements, gamma spectroscopy and ion radiochromatography. Trace metal contamination and molar activity were determined by ion chromatography. On a small scale, suitable for preclinical research, the process produced typically 3.2 GBq 64Cu in 2 mL solution from 9.4 ± 2.1 mg nickel-64 electroplated onto a gold target backing. The product had high molar activity (121.5 GBq/µmol), was free of trace metal contamination detectable by ion chromatography and has been used for many preclinical and clinical PET imaging applications.

64Cu production by 14 MeV neutron beam

64Cu is an emerging radionuclide of great interest in personalized nuclear medicine. It is produced by a cyclotron via the reaction 64Ni(p,n)64Cu. This production method increased during the last decades, because small biomedical cyclotrons can be easily installed close to the nuclear medicine department of a hospital. As a matter of fact, 64Ni is a very expensive target material. For this reason, an alternative 64Cu production method was investigated at ENEA by using the quasi-monochromatic 14 MeV fusion neutron beam made available at the Frascati Neutron Generator (FNG) located at the ENEA – Frascati Research Center. In particular, two nuclear reactions were studied: 65Cu(n,2n)64Cu and 64Zn(n,p)64Cu. The radiochemical analysis of the activated samples was performed at the ENEA-NMLNWM laboratory located in ENEA-Casaccia Research Center. The activity measurements were carried out at the ENEA-INMRI, located in the ENEA-Casaccia Research Center, with high metrological level conditions and by assuring their traceability to the 64Cu primary activity standard here developed and maintained. A prediction of the 64Cu production by means of the high-brilliance 14 MeV neutron source named Sorgentina is also discussed.

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.

Monte Carlo estimation of radiation fields and radio activations in the 64Ni solid target irradiation for 64Cu production and its validation with experimental findings

64Cu is an emerging theranostic radioisotope which is generating interest in the field of PET imaging and planning of therapy. A prototype solid target is being designed for producing 64Cu at RMC, BARC. This study evaluates radiation safety aspects involved in the use of the new solid target using FLUKA Monte Carlo code. The radiological hazards are quantified during the production of 64Cu and further handling of the target assembly for post irradiation processing. Analysis of ambient dose equivalent rates from the target assembly shows that during the sufficient quantity of 64Cu production, radiation fields outside the cyclotron vault at RMC BARC are below the allowed limit. The studies also confirm that the 4 h decay after the end of bombardment is suitable for post irradiation handling of the target.

64Cu enrichment using the Szilard-Chalmers effect – The influence of γ-dose

Cu is an important trace metal which plays a role in many biological processes. The radioisotope 64Cu is often used to study such processes. Furthermore, 64Cu finds applications in cancer diagnostics as well as therapy. For all of these applications 64Cu having high specific activity is needed. 64Cu can be produced in cyclotrons or in nuclear reactors. In this paper we study the effect of gamma dose on the production of 64Cu according to the Szilard-Chalmers reaction using Cu(II)-phthalocyanine as a target. For this purpose, irradiations were performed in the nuclear reactor of the Delft University of Technology using a novel irradiation facility helping to limit the dose produced by gammas present in the reactor pool. The obtained 64Cu activity yield was in general above 60% in accordance to the theoretical expected value. An increase in gamma dose has no significant influence on the obtained activity yield but increases the loss of Cu from Cu(II)-phthalocyanine up to 0.9% and hence decreases the specific activity that can be obtained. However, without optimisation, when reducing the gamma dose specific activities in the order of 30 TBq/g can be achieved.

Enhancement and Validation of a 3D-Printed Solid Target Holder at a Cyclotron Facility in Perth, Australia

A 3D-printed metal solid target using additive manufacturing process is a cost-effective production solution to complex and intricate target design. The initial proof-of-concept prototype solid target holder was 3D-printed in cast alloy, Al–7Si–0.6Mg (A357). However, given the relatively low thermal conductivity for A357 (max, 160 W/m·K), replication of the solid target holder in sterling silver (SS925) with higher thermal conductivity (max, 361 W/m·K) was investigated. The SS925 target holder enhances the cooling efficiency of the target design, thus achieving higher target current during irradiation. A validation production of 64Cu using the 3D-printed SS925 target holder indicated no loss of enriched 64Ni from proton bombardment above 80 µA, at 11.5 MeV.

Production, quality control and microPET analysis of novel solid-target based radionuclide 64Cu

Objective To briefly retrospect the production and quality control of 64Cu(n=9) in Department of Nuclear Medicine of Peking University Cancer Hospital in order to provide useful information for the further production and application of this novel radionuclide. Methods 64Ni(p, n)64Cu nuclide reaction was used for the 64Cu production. Firstly, a new electro-planting device for 64Ni planting was designed. HM-20 cyclotron was applied to irradiate the slice for 5-8 h. 64CuCl2 was purified, collected and injected into normal mice. MicroPET was conducted to monitor the metabolism in vivo. Results A new type of electro-planting device was designed and assembled. The enriched 64Ni target showed smooth, even, dense surface and without obvious pits and cracks. High specific 64Cu (1.3-4.1 GBq) can be collected after radio-chemical purification. 64Cu was finally dissolved in 0.01 mol/L HCl with high radionuclide purity (over 99.97%). MicroPET of 64CuCl2 in normal mice showed that the radioactivity was mainly accumulated in the liver. Conclusion A new and real-time observable device for 64Ni electro-plating has been designed and successfully used in the production of 64Cu with high specific activity. Key words: Nickel; Copper radioisotopes; Positron-emission tomography; Mice

A simple and efficient method to recover isotopically enriched Ni-64 from electrolytic solutions

Production of 64Cu via the proton irradiation of 64Ni, electrodeposited on a suitable backing substrate, remains the most common method to produce this emerging radionuclide. Some unforeseen cases arise when the electrodeposition does not work and the electrolytic solution needs to be reprocessed, but the presence of salt buffers makes it difficult to recover the nickel to prepare a fresh solution. The aim of this work was to develop a simple and efficient method to recover 64Ni from bath solutions.

Early Evaluation of Copper Radioisotope Production at ISOLPHARM.

The ISOLPHARM (ISOL technique for radioPHARMaceuticals) project is dedicated to the development of high purity radiopharmaceuticals exploiting the radionuclides producible with the future Selective Production of Exotic Species (SPES) Isotope Separation On-Line (ISOL) facility at the Legnaro National Laboratories of the Italian National Institute for Nuclear Physics (INFN-LNL). At SPES, a proton beam (up to 70 MeV) extracted from a cyclotron will directly impinge a primary target, where the produced isotopes are released thanks to the high working temperatures (2000 °C), ionized, extracted and accelerated, and finally, after mass separation, only the desired nuclei are collected on a secondary target, free from isotopic contaminants that decrease their specific activity. A case study for such project is the evaluation of the feasibility of the ISOL production of 64Cu and 67Cu using a zirconium germanide target, currently under development. The producible activities of 64Cu and 67Cu were calculated by means of the Monte Carlo code FLUKA, whereas dedicated off-line tests with stable beams were performed at LNL to evaluate the capability to ionize and recover isotopically pure copper.

Small-scale production of 67Cu for a preclinical study via the 64Ni(α, p)67Cu channel

IntroductionCopper-67 is an attractive beta emitter for targeted radionuclide therapy. However, the availability of 67Cu limits its potential use in a wide range of applications. In this study, we propose an easy small-scale production of 67Cu using 64Ni target for a preclinical study. Methods67Cu was produced from an electrodeposited 64Ni target via the 64Ni(α, p)67Cu-reaction with a 36 MeV alpha beam at 15 eμA (electrical microampere) conducted for 7 h. The chemical separation process of 67Cu from the 64Ni target was performed following by our routine procedure of 64Cu production using cation exchange resin, AG50W-X8, with minor modification. The target and its holder were redesigned in the preparation. ResultsThe 67Cu product was obtained with a yield of 55 ± 10 MBq at the end of bombardment (EOB), and the yield was 527 ± 96 kBq/μAh at the EOB. The copper impurity in the product was low (0.71 ± 0.21 μg) and the product was suitable for a preclinical study. ConclusionsWe produced 67Cu with sufficient activity and quality for a preclinical study using a 64Ni-target. This production method also showed advantages as a routine method, i.e., shorten the processing time, reducing the radiation exposure and ready target recycling, when compared with that of a conventional Zn-target used for 67Cu production.

Concurrent spectrometry of annihilation radiation and characteristic gamma-rays for activity assessment of selected positron emitters

A method is described to determine the activity of non-pure positron emitters in a radionuclide production environment by assessing the 511keV annihilation radiation concurrently with selected γ-lines, using a single High-Purity Germanium (HPGe) detector. Liquid sources of 22Na, 52Fe, 52mMn, 61Cu, 64Cu, 65Zn, 66Ga, 68Ga, 82Rb, 88Y, 89Zr and 132Cs were prepared specifically for this study. Acrylic absorbers surrounding the sources ensured that the emitted β+-particles could not escape and annihilate away from the source region. The absorber thickness was matched to the maximum β+ energy for each radionuclide. The effect on the 511keV detection efficiency by the non-homogeneous distribution of annihilation sites inside the source and absorber materials was investigated by means of Monte Carlo simulations. It was found that no self-absorption corrections other than those implicit to the detector calibration procedure needed to be applied. The medically important radionuclide, 64Cu, is of particular interest as its strongest characteristic γ-ray has an intensity of less than 0.5%. In spite of the weakness of its emission intensity, the 1346keV γ-line is shown to be suitable for quantifying the 64Cu production yield after chemical separation from the target matrix has been performed.

Murine Lymphocyte Labeling by 64Cu-Antibody Receptor Targeting for In Vivo Cell Trafficking by PET/CT.

This protocol illustrates the production of 64Cu and the chelator conjugation/radiolabeling of a monoclonal antibody (mAb) followed by murine lymphocyte cell culture and 64Cu-antibody receptor targeting of the cells. In vitro evaluation of the radiolabel and non-invasive in vivo cell tracking in an animal model of an airway delayed-type hypersensitivity reaction (DTHR) by PET/CT are described. In detail, the conjugation of a mAb with the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) is shown. Following the production of radioactive 64Cu, radiolabeling of the DOTA-conjugated mAb is described. Next, the expansion of chicken ovalbumin (cOVA)-specific CD4+ interferon (IFN)-γ-producing T helper cells (cOVA-TH1) and the subsequent radiolabeling of the cOVA-TH1 cells are depicted. Various in vitro techniques are presented to evaluate the effects of 64Cu-radiolabeling on the cells, such as the determination of cell viability by trypan blue exclusion, the staining for apoptosis with Annexin V for flow cytometry, and the assessment of functionality by IFN-γ enzyme-linked immunosorbent assay (ELISA). Furthermore, the determination of the radioactive uptake into the cells and the labeling stability are described in detail. This protocol further describes how to perform cell tracking studies in an animal model for an airway DTHR and, therefore, the induction of cOVA-induced acute airway DHTR in BALB/c mice is included. Finally, a robust PET/CT workflow including image acquisition, reconstruction, and analysis is presented. The 64Cu-antibody receptor targeting approach with subsequent receptor internalization provides high specificity and stability, reduced cellular toxicity, and low efflux rates compared to common PET-tracers for cell labeling, e.g.64Cu-pyruvaldehyde bis(N4-methylthiosemicarbazone) (64Cu-PTSM). Finally, our approach enables non-invasive in vivo cell tracking by PET/CT with an optimal signal-to-background ratio for 48 h. This experimental approach can be transferred to different animal models and cell types with membrane-bound receptors that are internalized.