Production of 64Cu and 67Cu with accelerator neutrons by deuterons and their separation from zinc

The ⁶⁴Cu/⁶⁷Cu pair is an ideal set of theranostic radionuclides for treating patients based on their genetic profiles. We propose a novel production route for this radionuclide pair using accelerator-generated neutrons. We report experimental measurements of the absolute activity and radionuclide purity of ⁶⁴Cu and ⁶⁷Cu, produced by irradiating ⁶⁴Zn and ⁶⁸Zn with these neutrons. The measured results were consistent with simulated values. ⁶⁴Cu and ⁶⁷Cu were separated from the irradiated natural Zn and ⁶⁸Zn using sublimation and column separation techniques. The production methods for ⁶⁴Cu and ⁶⁷Cu developed in this study are expected to enhance their availability in an economically sustainable manner.

1 Introduction

Recently, there has been increased interest in personalized nuclear medicine. Currently, a variety of radiopharmaceuticals are administered to cancer patients for therapeutic and diagnostic purposes (1–3). These radiopharmaceuticals contain radionuclides with similar chemical and biochemical properties that allow them to target specific diseases. The term “theranostic” refers to the combined use of diagnostic and therapeutic agents containing these radionuclides (4).

When radioisotopes are used to treat cancer patients, real-time imaging is performed using pharmaceutical compounds labeled with gamma-ray-emitting diagnostic radioisotopes. This allows the distribution of pharmaceutical compounds in the patient's body to be assessed, and the appropriateness of the treatment and dosage of the therapeutic drug to be evaluated. The ability to monitor the distribution of therapeutic radioisotopes in real time enables the understanding of specific patient conditions and characteristics, and the selection of the most effective treatment through theranostics, facilitating personalized medicine (1–3).

The concept of using therapeutic and diagnostic radioisotopes in cancer treatment was first proposed in 1946 with the use of β⁻- and γ-emitting ¹³¹I (T_1/2 = 8.0 d) for the treatment of thyroid cancer. Currently, 3.7–5.55 GBq of ¹³¹I is used for thyroid cancer treatment (3, 5). Common radioisotope pairs used for therapeutic and diagnostic purposes include ¹³¹I (¹²³I, ¹²⁴I), ⁹⁰Y (¹¹¹In, ⁸⁶Y), ¹⁷⁷Lu (¹¹¹In), ²¹²Pb (⁶⁸Ga, ⁸⁶Y), ²²³Ra (^99mTc, ¹⁸F), ²²⁵Ac (⁶⁸Ga, ⁸⁶Y), ²²⁷Th (⁸⁹Zr), ¹⁸⁶Re (^99mTc), and ⁶⁷Cu (⁶⁴Cu) (6). Diagnostic radioisotopes are indicated in parentheses.

Concurrently, the ⁶⁴Cu/⁶⁷Cu pair is an emerging set of radionuclides that are ideal for use in therapeutic diagnostics (theranostics) (7–11) due to their identical chemical and biological properties, the ability of copper to form diverse coordination complexes with small molecules, antibodies, and proteins, and the favorable physical properties of ⁶⁴Cu and ⁶⁷Cu (4–6). Specifically, ⁶⁴Cu has a half-life of 12.7 h and decays via positron emission (17.5%) with a maximum energy of 0.653 MeV, β⁻-rays emission (38.5%) with a maximum energy of 0.579 MeV, and electron capture (44.0%) (12, 13) as shown in Figure 1A, making it suitable for positron emission tomography (PET). ⁶⁷Cu has a half-life of 61.8 h and emits β⁻-rays with maximum energies of 0.377 MeV (57%), 0.468 MeV (22%), and 0.562 MeV (20%) (13, 14), as illustrated in Figure 1B. These β⁻-rays have a range of approximately 3 mm in water (15). Furthermore, ⁶⁷Cu emits 91, 93, and 185 keV γ-rays, enabling its detection by gamma cameras. Consequently, ⁶⁷Cu is well-suited for diagnostic imaging and internal radiotherapy. Therefore, increasing Cu availability is crucial for the development of radiopharmaceuticals that target various diseases (6–8).

Figure 1

Figure 1. Decay schemes of ⁶⁴Cu (A) and ⁶⁷Cu (B), reproduced from references (12) and (14), respectively.

Numerous studies have been on the production of ⁶⁷Cu using the ⁶⁷Zn(n,p)⁶⁷Cu reaction in reactors (16). Additionally, studies have been conducted on the production of ⁶⁷Cu using the ⁶⁸Zn(p,2p)⁶⁷Cu (16, 17), ⁶⁸Zn(γ,p)⁶⁷Cu (18, 19), ⁶⁷Zn(n,p)⁶⁷Cu (20), ⁷⁰Zn(p,α)⁶⁷Cu (16, 21), and ⁷⁰Zn(d,αn)⁶⁷Cu (22) reactions in accelerators. Recently, a significant improvement in the accessibility of ⁶⁷Cu was achieved using the ⁶⁸Zn(γ,p)⁶⁷Cu reaction at the Argonne National Laboratory Low Energy Accelerator Facility (9). This resulted in a production yield of over 62.9 GBq after 53.5 h of irradiation.

⁶⁴Cu has also been produced in reactors by the ⁶³Cu(n,γ)⁶⁴Cu reaction and in accelerators by the ⁶⁴Ni(p,n)⁶⁴Cu, ⁶⁴Ni(d,2n)⁶⁴Cu, ⁶⁴Zn(d,2p)⁶⁴Cu, ⁶⁶Zn(d,α)⁶⁴Cu, ⁶⁸Zn(p,αn)⁶⁴Cu, and ⁶⁴Zn(n,p)⁶⁴Cu reactions. The most commonly adopted production route is ⁶⁴Ni(p,n)⁶⁴Cu (23). Indeed, the production of high-quality ⁶⁴Cu with 8.7 GBq at EOI was achieved by bombarding a highly enriched ⁶⁴Ni target (enrichment 99.53%) with a 20 μA proton beam for a period of 4 h (24).

Kin et al. previously proposed a novel route for producing ⁶⁷Cu and ⁶⁴Cu using accelerator neutrons with energies ranging from a few MeV to approximately 40 MeV via the ⁶⁸Zn(n,n'p)⁶⁷Cu and ⁶⁸Zn(n,d)⁶⁷Cu reactions, as well as the ⁶⁴Zn(n,p)⁶⁴Cu reaction (15), based on the following results obtained by them: Kin et al. measured the activation cross-sections of ⁶⁴Cu and ⁶⁷Cu by bombarding natural zinc with 14 MeV neutrons. The production yields of ⁶⁴Cu and ⁶⁷Cu by accelerator neutrons from ^natC(d,n) with 40 MeV 5 mA deuterons were estimated using the results and the evaluated cross-sections of the Zn isotopes. The estimated ⁶⁴Cu yield was 1.8 TBq (175 g ⁶⁴Zn) after 12 h of irradiation. At the end of the two-day irradiation period, the estimated yield of ⁶⁷Cu from ⁶⁷Zn(n,p)⁶⁷Cu was 249 GBq (184 g ⁶⁷Zn), and the estimated yield from ⁶⁸Zn(n,n'p)⁶⁷Cu and ⁶⁸Zn(n,d)⁶⁷Cu were 287 GBq (186 g ⁶⁸Zn).

Subsequently, production yield studies of ⁶⁷Cu and ⁶⁴Cu were conducted (25–28), and an apparatus for the separation and purification of these radionuclides from neutron-irradiated ZnO was constructed. Kawabata et al. initially established a fundamental separation and purification procedure, using only the column separation technique for ⁶⁴Cu and ⁶⁷Cu from neutron-irradiated ^natZnO and ⁶⁴ZnO 5 g with high separation efficiency and successful labelling, together with high recovery of Zn samples. The column separation technique was employed in the determination of the biodistribution of ⁶⁷CuCl₂ in colorectal tumor-bearing mice by Sugo, Hashimoto, Kawabata et al. (26). In the latest study, Kawabata et al. developed a combined thermal and column chromatography separation to separate ⁶⁴Cu and ⁶⁷Cu from 55.4 g of natural zinc that had been irradiated with accelerator neutrons. Sublimation removed 99% of the zinc, with 97% physically recovered for reuse. Following the removal of most of the zinc by thermal separation, the residual zinc containing ⁶⁷Cu was in the order of milligrams. The residual zinc was further purified using chromatographic resins (28, 29). The experiments yielded a total separation efficiency of 73% for ⁶⁷Cu.

In this study, we measured the absolute activity and radionuclidic purity of ⁶⁴Cu and ⁶⁷Cu produced by neutron irradiation of ⁶⁴ZnO and ⁶⁸ZnO. The measured values of ⁶⁴Cu and ⁶⁷Cu were compared with the simulation results. In addition, new sublimation and column separation apparatuses were installed at the Research Center for Accelerator and Radioisotope Science (RARiS) facility at Tohoku University.

2 Materials and methods

The schematic diagram for the production and separation of ⁶⁴Cu and ⁶⁷Cu from neutron-irradiated ⁶⁴Zn and ⁶⁸Zn is shown in Figure 2.

Figure 2

Figure 2. Schematic diagram of ⁶⁷Cu and ⁶⁴Cu production using accelerator neutrons generated by deuterons, and their subsequent separation from ⁶⁸Zn and ⁶⁴Zn. The accelerator neutrons were produced via the ^natC(d,n) reaction in a vacuum. The ^natC target was placed in a vacuum chamber and equipped with a rotating cooling system to manage the thermal load associated with high-intensity deuteron beams.

2.1 Production of ⁶⁷Cu and ⁶⁴Cu

Copper−64 and Copper-67 were produced by irradiating enriched samples of ⁶⁴Zn and ⁶⁸Zn with accelerator neutrons through the reactions ⁶⁴Zn(n,p)⁶⁴Cu, ⁶⁸Zn(n,n’p)⁶⁷Cu, and ⁶⁸Zn(n,d)⁶⁷Cu. Accelerator neutrons were generated via the ^natC(d,n) reaction. The natural carbon target (^natC), with a thickness of 10 mm and a diameter of 27 mm, was placed within a deuteron beam duct (vacuum). The samples, consisting of 0.295 g ⁶⁴ZnO and 0.363 g ⁶⁸ZnO, each with a diameter of 10 mm, were placed in air at 0° with respect to the deuteron beam direction. Prior to irradiation, the samples were pressed into pellets and sintered at 150°C for 40 min. The isotopic composition of the ⁶⁴Zn sample was 99.935% and that of the ⁶⁸Zn sample was: ⁶⁴Zn (0.03 at%), ⁶⁶Zn (0.16 at%), ⁶⁷Zn (0.62 at%), ⁶⁸Zn (99.16 at%), and ⁷⁰Zn (0.03 at%). Niobium foils, 10 mm in diameter and 0.1 mm thick, were positioned on either side of the ⁶⁴ZnO and ⁶⁸ZnO pellets to monitor the neutron yield. A typical description of the experimental setup for irradiation of Zn samples is given in (28).

Copper-64 was produced by irradiating ⁶⁴ZnO with neutrons for three hours. Neutrons were generated using 41 MeV deuterons with an average beam current of 0.11 μA, provided by the AVF cyclotron at the Takasaki Ion Accelerator Advanced Radiation Applications Facility (TIARA), National Institutes for Quantum and Radiological Science and Technology (30). Copper-67 was produced by irradiating ⁶⁸ZnO with neutrons for three minutes. Neutrons were generated using 52 MeV deuterons with an average beam current of 0.379 μA, provided by the AVF cyclotron at RARiS, Tohoku University (31). The 52 MeV deuteron beam is the highest energy currently achievable with these AVF cyclotrons.

The absolute activity and radionuclide purity of ⁶⁴Cu and ⁶⁷Cu were, respectively, determined by measuring the 1,346 keV γ-ray intensity from the decay of ⁶⁴Cu and the 185 keV γ-ray intensity from the decay of ⁶⁷Cu. The absolute activity of ⁶⁴Cu and ⁶⁷Cu depends on the excitation function for the reaction of ⁶⁴Zn(n,p)⁶⁴Cu and ⁶⁸Zn(n,n’p)⁶⁷Cu and the ⁶⁸Zn(n,d)⁶⁷Cu. The excitation functions evaluated for reactions such as ⁶⁴Zn(n,p)⁶⁴Cu, ⁶⁴Zn(n,n’p)⁶³Cu, and ⁶⁴Zn(n,d)⁶³Cu are shown in Figure 3A, and those evaluated for reactions such as ⁶⁸Zn(n,n'p)⁶⁷Cu, ⁶⁸Zn(n,d)⁶⁷Cu, and ⁶⁸Zn(n,4n)⁶⁵Zn are shown in Figure 3B. These figures highlight the importance of measuring the yields and radionuclide purities of ⁶⁴Cu and ⁶⁷Cu over a range of neutron (or deuteron) energies.

Figure 3

Figure 3. (A) evaluated excitation functions for reactions such as ⁶⁴Zn(n,p)⁶⁴Cu, ⁶⁴Zn(n,n’p)⁶³Cu, and ⁶⁴Zn(n,d)⁶³Cu during neutron irradiation of enriched ⁶⁴Zn (32). (B) Evaluated excitation functions for reactions including ⁶⁸Zn(n,n′p)⁶⁷Cu, ⁶⁸Zn(n,d)⁶⁷Cu, and ⁶⁸Zn(n,4n)⁶⁵Zn during neutron irradiation of enriched ⁶⁸Zn (32). ⁶⁵Ni (T_1/2 = 2.5 h) and ⁶⁵Zn (T_1/2 = 244 d) decay to ⁶⁵Cu (a stable nuclide), while ^69mZn (T_1/2 = 14 h) decays to ⁶⁹Ga (also stable). The excitation functions for the ⁶⁸Zn(n,n′p)⁶⁷Cu, ⁶⁸Zn(n,d)⁶⁷Cu, and ⁶⁴Zn(n,p)⁶⁴Cu reactions indicate very low production of Zn-based impurity radionuclides. The most probable 14 MeV neutron energy generated by the ^natC(d,n) reaction using 40 MeV deuterons is indicated by the thin solid line (33).

The accelerator neutrons used to produce ⁶⁴Cu and ⁶⁷Cu exhibited the following characteristics. First, a neutron energy spectrum can be obtained from the C(d,n) reaction, which is suitable for the efficient production of these radionuclides, by appropriately selecting the deuteron energy (E_in) (27, 28). Second, neutrons are predominantly emitted in the forward direction relative to the deuteron beam axis (34–36), resulting in nearly complete irradiation of the enriched ⁶⁴Cu or ⁶⁸Zn placed immediately behind the ^natC target (36). Notably, SPIRAL2 at GANIL in France will produce 10¹⁵ neutrons per second (n/s) through the ^natC(d,n) reaction using 40 MeV, 5 mA deuterons (33).

2.1.1 Absolute activity and radionuclide purity of ⁶⁴Cu and ⁶⁷Cu

The measured absolute activities and radionuclide purities of ⁶⁴Cu and ⁶⁷Cu were compared with the evaluated values, as follows:

First, we note that a single radionuclide, B, is produced via a neutron-induced reaction on the Zn isotope A in the enriched ⁶⁴Zn or ⁶⁸Zn samples. This is represented by the A(n,x)B reaction. Next, the yield rate Y_a of radionuclide B produced from isotope A via a reaction channel, α ≡ α(A, B), of the A(n,x)B reaction was derived as:

$\begin{array}{c}{Y}_{\alpha }=\underset{E_{\min }}{\overset{E_{\max }}{\int }}{\sigma }_{\alpha }(E_n)f_n(E_n)d{E}_n,\end{array}(1)$

where σ_α(E_n) is the excitation function at neutron energy E_n for the channel α, and f_n(E_n) is the neutron fluence in the sample. In Equation 1, the limits E_min and E_max correspond to the energy range of the neutrons produced by the ^natC(d,n) reaction in a 10-mm-thick carbon target. Note that E_min should be set to the threshold energy $E_{\mathrm{th}-\alpha }$ for channel α if E_min is lower than this threshold. Excitation functions σ_α(E_n) were obtained from the production cross sections provided in the fifth version of the Japanese Evaluated Nuclear Data Library (JENDL-5) (37). The neutron fluence f_n(E_n) was derived from a particle transport simulation using the Particle and Heavy Ion Transport code System (PHITS) (38), which accounted for neutron propagation from the carbon target—where neutrons are produced with energy $E_n^{\mathrm{\prime }}$ and angle ${\mathrm{\Omega }}_n^{\mathrm{\prime }}$ via the ^natC(d,n) reaction—to the Zn sample. The fluence of the produced neutrons at position r in the target is given by:

$\begin{array}{c}{\overline{f}}_n(E_n^{\mathrm{\prime }},{\mathrm{\Omega }}_n^{\mathrm{\prime }},r)=N_{\mathrm{C}}\underset{0}{\overset{E_{\mathrm{in}}}{\int }}{\sigma }_{(d,n)}(E_d,E_n^{\mathrm{\prime }},{\mathrm{\Omega }}_n^{\mathrm{\prime }})f_d(E_d,\mathit{r})d{E}_d,\end{array}(2)$

where $N_{\mathrm{C}}$ is the number of carbon nuclei in the target, $E_{\mathrm{in}}=41$ and 52 MeV are the incident deuteron energies, ${\sigma }_{(d,n)}$ are the neutron production cross sections obtained from JENDL-5, and $f_d$ is the deuteron fluence at position r, normalized per incident deuteron. The PHITS simulation accounted for the attenuation of deuteron fluence in the target, including the corresponding decrease in deuteron energy. The neutron fluence $f_n$ in the Zn sample was calculated as the component of ${\overline{f}}_n$ directed toward the sample. By setting the number of deuterons N_d irradiating the sample, isotopic abundance R_A of isotope A in the Zn sample, and particle density ρ of Zn, the total yield Y(B) of radionuclide B in the sample can be expressed as:

$\begin{array}{c}Y(B)=N_d\sum _A{R}_A\rho \sum _{\alpha \in B}{Y}_{\alpha },\end{array}(3)$

where $\alpha \in B$ indicates that the summation includes all reaction channels α through which isotope A can produce radionuclide B. Here, A refers to one of the five stable Zn isotopes: ⁶⁴Zn, ⁶⁶Zn, ⁶⁷Zn, ⁶⁸Zn, and ⁷⁰Zn, and B denotes one of Cu or Zn radionuclides listed in Reference (39). Furthermore, Ga radionuclides were evaluated as products B by replacing neutrons with protons in the above equations. Finally, the yield was multiplied by the saturation factor to evaluate the amount produced at the EOI. Stable isotopes of ⁶³Cu and ⁶⁵Cu can be produced by reactions such as ⁶⁴Zn(n,n'p)⁶³Cu and ⁶⁸Zn(n,p3n)⁶⁵Cu, respectively. Their production reduced the specific activity of the products ⁶⁴Cu and ⁶⁷Cu. Consequently, an absolute yield evaluation of these isotopes is imperative, because they are not detectable by radiation detectors.

2.2 Separation of ⁶⁷Cu and ⁶⁴Zn from irradiated ⁶⁸Zn and ^natZn

We developed a new sublimation and column chromatography separation apparatus to be installed in an existing hot cell at the Research Center for Accelerator and Radioisotope Science (RARiS) facility at Tohoku University. The apparatus was designed for the production and separation/purification of ⁶⁴Cu and ⁶⁷Cu using the cyclotron at Tohoku University. To obtain ⁶⁷Cu and ⁶⁴Cu from irradiated ⁶⁸Zn and ^natZn, respectively, the same separation apparatus was used for both sublimation and column chromatography because both irradiated samples contained common impurity radionuclides belonging to Cu and Zn in addition to the desired ⁶⁷Cu and ⁶⁴Cu.

2.2.1 Sublimation separation of Zn

The initial separation of ⁶⁷Cu (or ⁶⁴Cu) in the milligram range from neutron-irradiated bulk ⁶⁸Zn (or ^natZn) was achieved using the sublimation method, originally developed by the Argonne National Laboratory (ANL) group (40). We developed a vertical-type sublimation apparatus (Figure 4) instead of the horizontal-type due to the inadequate effective dimensions within the cell.

Figure 4

Figure 4. Layout of the sublimation separation apparatus for an irradiated Zn sample. (1) Irradiated Zn sample containing ⁶⁷Cu activity, (2) quartz beads, (3) sublimated Zn element, (4) vacuum chamber, (5) electric tubular furnace, (6) electric leak valve, (7) vacuum gauge, (8) CZT γ-ray detector, (9) cold trap, (10) turbomolecular pump, (11) motor, (12) butterfly valve.

Cooling devices were attached to the upper flange and top of the vacuum vessel to facilitate the recovery of sublimated Zn inside the system. Sublimation is an effective method for the separation of Zn and Cu due to the substantial difference in their boiling points: The boiling points of Zn and Cu are 907°C and 2,562°C, respectively. In this study, sublimation experiments were performed at temperatures of 500 and 600°C under a vacuum of 2.0 × 10⁻⁵ hectopascal (hPa) to determine the optimal temperature for maximizing Zn sublimation while reducing the amount of distilled Cu. This apparatus can separate more than 40 g of Zn via thermal separation.

The furnace temperature can be controlled remotely, and the separation vessel can be raised or lowered remotely outside the cell. Two ⁶⁷Cu activities were produced by irradiating 43.6 g of ^natZn, consisting of three pellets, with accelerator neutrons, and bombarding an enriched ⁶⁸Zn pellet (3.93 g) with photons. Accelerator neutrons and photons were generated by a cyclotron and an electron linear accelerator (linac), respectively, at Tohoku University. The irradiated Zn samples were placed in a quartz tube with quartz beads (7 mm ϕ), which were dispersed between the pellets to serve as fillers and increase the sublimation surface among samples comprising more than 10 g of multiple pellets to increase the sublimation surface area of the Zn and shorten the sublimation time (28). γ-ray spectra were recorded every 3 min using a CZT detector while heating, in order to monitor changes in the activity of ⁶⁷Cu (185 keV) and ⁶⁵Zn (1,116 keV) over time. After heating was stopped, the furnace was lowered to allow the system to cool below 200°C, after which the equipment was returned to atmospheric pressure. The quartz components were then removed and weighed to determine the Zn deposition and sublimation efficiency.

The efficiency of sublimation separation of irradiated Zn was determined online by comparing the activity of ⁶⁵Zn (1,116 keV γ-ray) measured with the CZT detector before and after separation. The Zn accumulated in the quartz tube during the sublimation of Cu from the irradiated Zn was collected for recycling. Prior to collection, the distribution of accumulated Zn was determined by measuring the ⁶⁵Zn (1,116 keV) signal using a high-purity germanium (HPGe) detector. The separation yield of Zn was calculated using a gravimetric method.

The non-radioactive Cu present in the Zn sample was removed prior to irradiation, because it lowers the specific activity of the ⁶⁴Cu or ⁶⁷Cu product (28). The zinc samples were sublimated at 650°C for 120 min under vacuum to prevent oxidation. The sublimated zinc was subsequently collected, melted, and prepared as pellets for irradiation. This method can also be applied to the recycling of enriched zinc after the separation of ⁶⁷Cu (⁶⁴Cu).

The copper remaining in the test tube was further purified using commercially available resins, as described below.

2.2.2 Purification of ⁶⁷Cu by column chromatography

The purification scheme is illustrated in Figure 5. Two CU Resin cartridges (2 ml and 1 ml, TrisKem International) and one TK201 cartridge (2 ml, TrisKem International) were pre-conditioned with 30 ml of 0.01 M HCl (15 ml for the 1 ml resin) and 30 ml of 8 M hydrochloric acid, respectively. A 1 ml CU Resin cartridge was placed below the 2 ml cartridge as a guard column to retain any copper that may have leaked from the larger cartridge. After the sublimation of bulk Zn, quartz beads were added to the test tube to fill the void space, and 8 M hydrochloric acid was added until the tube opening was submerged, —typically requiring approximately 15 ml, —to ensure the complete dissolution of the copper and Zn residues. Dissolution was enhanced by applying ultrasonic waves for 10 min. The solution containing dissolved Cu and Zn was transferred to another container. The test tubes were washed with ultrapure water under ultrasonic agitation for 10 min. The resulting solution was filtered through a glass filter to remove insoluble residues and ash. The pH of the filtrate was adjusted to pH 2–3 using a NaOH solution.

Figure 5

Figure 5. Purification steps of ⁶⁷Cu from Zn.

This pH-adjusted solution was loaded onto the CU Resin cartridge to adsorb ⁶⁷Cu, followed by washing with 45 ml of 0.01 M HCl to remove residual Zn and other impurities. The flow rate was maintained at 1.0 ml/min, controlled by a peristaltic pump. After trapping copper in the CU Resin, 8 ml of 8 M HCl was passed through the column to elute ⁶⁷Cu, which was then reabsorbed onto the TK201 resin. The final ⁶⁷Cu product was eluted with 14 ml of 0.05 M HCl, followed by acid removal through evaporation. The same purification procedure was use to separate ⁶⁴Cu from ⁶⁴Zn.

The total time required for sublimation and chromatography steps was 8 h, each step requiring 4 h.

3 Results

We discuss these results by referring to the γ-ray branching ratios obtained from the decay of ⁶⁷Cu, as shown in Figure 1A.

3.1 Absolute activity and radionuclide purity of ⁶⁴Cu and ⁶⁷Cu

Figure 6 shows the γ-ray spectrum of irradiated ⁶⁸Zn. The observed γ-ray peaks originate from the decay of ⁶⁷Cu (91, 93, 185, 209, 300, and 394 keV), ⁶⁵Ni (T_1/2 = 2.52 h; 366, 508, 610, and 1,116 keV), ⁶⁵Zn (T_1/2 = 244 d; 1,116 keV), and ^69mZn (T_1/2 = 13.8 h; 439 keV). The isotope assignments of the observed γ-rays were based on their energies, decay curves, and known branching ratios.

Figure 6

Figure 6. γ-ray spectrum of the neutron irradiated ⁶⁸ZnO using a deuteron beam of 52 MeV. The γ-ray peaks originate from the decays of ⁶⁷Cu (open circles), ⁶⁵Ni (open triangles), ^69mZn (filled diamond), and ⁶⁵Zn (filled square).

The activity of ⁶⁷Cu and the impurity of ⁶⁵Zn (as well as ⁶⁴Cu and the impurities of ⁶¹Cu, ⁶²Zn, and ⁶³Zn) at EOI were determined by considering the branching ratios of the observed 185 keV and 1,116 keV (and 1,346 keV and 656 keV, 597 keV, and 670 keV) γ-rays (41), as well as the γ-ray detection efficiency of the HPGe detector, which was calibrated using a standard ¹⁵²Eu γ-ray source. The self-absorption of the γ-rays in the irradiated ⁶⁸Zn sample was corrected using the photon cross-sectional database provided by the National Institute of Standards and Technology (42). The calculated yields of ⁶⁷Cu and ⁶⁵Zn (along with ⁶⁴Cu, ⁶¹Cu, ⁶²Zn, and ⁶³Zn) at EOI, obtained using the radionuclide production rates, irradiation time, and deuteron beam intensity, are presented in Table 1. The calculated and measured yields were in good agreement within an uncertainty of ±20%. The total systematic uncertainty in the calculated yields was estimated to be 23%, taking into account the uncertainty of 18% in the measured neutron data for the ^natC(d,n) reaction (43), and an assumed 15% uncertainty in the evaluated cross sections. The total systematic uncertainty in the experimental values was calculated to be 12%, based on the estimated uncertainties in the distance between the carbon target and the sample, spatial distribution of the deuteron beam intensity and diameter, and γ-ray detection efficiency of the HPGe detector.

Table 1

Table 1. The measured and calculated activities of ⁶⁷Cu, ⁶⁴Cu, ⁶⁵Zn, ^69mZn, ⁶⁵Ni, ⁶⁶Ga, and ⁶⁷Ga at the EOI of enriched ⁶⁸Zn at E_in = 52 and 40 MeV are shown.

The measured activity of ⁶⁷Cu at E_in = 52 MeV at EOI was 1.23 ± 0.05 kBq, which was approximately 3.2 times higher than 0.383 ± 0.02 kBq measured at E_in = 40 MeV. In contrast, the measured yield of ⁶⁵Zn at 52 MeV was 2.9 ± 0.16 Bq, which was approximately 12 times higher than 0.25 ± 0.02 Bq, measured at 40 MeV. The substantial increase in ⁶⁷Cu yield observed when employing 52 MeV deuteron beams underscores the practical advantage of expanding the availability of ⁶⁷Cu, ⁶⁵Zn was separated from ⁶⁷Cu via sublimation.

Figure 7 shows the gamma-ray spectrum of irradiated ⁶⁴Zn. The observed gamma-ray peaks originate from the decay of ⁶⁴Cu (511 and 1346 keV), ⁶¹Cu (T^1/2 = 3.32 h, 656 keV), ⁶²Zn (T^1/2 = 9.26 h, 548.4 and 596.6 keV) ⁶³Zn (T^1/2 = 38.5 minutes. 669.6 and 962.1 keV). The measured activities of ⁶⁴Cu, ⁶¹Cu, ⁶²Zn, and ⁶³Zn at Eⁱⁿ = 41 MeV at the EOI were 6.61  ± 0.42 kBq, 59.4 ± 4.7 Bq, 214 ± 12 Bq, and 39.5 ± 3.6 kBq, respectively, as listed in Table 2. ⁶⁴Cu produced the low amount level of ⁶¹Cu radioactive waste. Copper-61 is produced by the ⁶⁴Zn(n,p3n)⁶¹Cu reaction. Short lived impurity radionuclide ⁶²Zn and ⁶³Zn can be separated by sublimation process.

Figure 7

Figure 7. γ-ray spectrum of the neutron irradiated ⁶⁴ZnO using a deuteron beam of 41 MeV. The γ-ray peaks come from the decays of ⁶⁴Cu (filled circle), ⁶¹Cu (open square), ⁶²Zn (filled tringle), and ⁶³Zn (open diamond).

Table 2

Table 2. The measured and calculated activities of ⁶⁴Cu, ⁶¹Cu, ⁶²Zn, ⁶³Zn, and ⁶⁵Zn at the EOI of enriched ⁶⁴Zn at E_in = 41 MeV are shown, along with the ratio of calculated numbers of atoms for non-radioactive ⁶³Cu and ⁶⁵Cu relative to ⁶⁴Cu.

3.2 Separation

Figure 8 shows the γ-ray spectrum measured after the purification of the neutron irradiated ^natZnO. The γ-ray peaks come from the decays of ⁶⁴Cu and ⁶⁷Cu. A ⁶⁵Zn radionuclide impurity in the final ⁶⁴Cu product was below the detection limit of gamma-ray spectrometry providing ⁶⁵Zn/⁶⁴Cu\0.01%.

Figure 8

Figure 8. γ-ray spectrum measured after the purification of the neutron irradiated ^natZnO using a deuteron beam of 40 MeV. The γ-ray peaks come from the decays of ⁶⁴Cu (filled circle) and ⁶⁷Cu (open circle).

The Zn separation yield was determined using a gravimetric method. Using this apparatus, thermal separation was performed on 43.6 g of irradiated natural zinc, achieving a sublimation rate of 99% and recovering 94% of the zinc in a reusable form. At the end of the thermal separation process, the Cu-67 yield reached 87%, and subsequent chemical purification resulted in an overall Cu-67 recovery yield of 79%. For 3.932 g of enriched ⁶⁸Zn, the separation efficiency was 99% by sublimation and 95% by column chromatography, with a total separation efficiency of 94%. The sublimation time for ^natZn was 93 min, whereas that for ⁶⁸Zn was 20 min. In both samples, the amount of ⁶⁷Cu remaining in the non-sublimated material was less than 50 mg, which enabled subsequent purification by chromatography.

4 Discussion

The ⁶⁴Cu/⁶⁷Cu pair is an emerging set of radionuclides for use in theragnostic due to their identical chemical and biological properties and their favorable physical properties. Therefore, increasing the availability of ⁶⁷Cu and ⁶⁴Cu is crucial for developing radiopharmaceuticals that target various diseases. The novel production method of both ⁶⁷Cu and ⁶⁴Cu using accelerator neutrons provided from accelerators was previously proposed.

The absolute activity and radionuclidic purity of ⁶⁴Cu and those of ⁶⁷Cu were measured for the first time using enriched ⁶⁴ZnO and ⁶⁸ZnO at a deuteron energy of 41 MeV and 52 MeV, respectively. High radionuclidic purity of ⁶⁴Cu was produced with a minimum level of radioactive waste. The ⁶⁷Cu activity at 52 MeV was found to be 3.2 times higher than that at 40 MeV. The measured radioactivity and radionuclidic purity of ⁶⁴Cu and ⁶⁷Cu were in good agreement with the simulation based calculated values. The simulation further estimated the unmeasured yields of non-radioactive ⁶³Cu and ⁶⁵Cu relative to ⁶⁴Cu and ⁶⁷Cu at 41 MeV and 52 MeV, respectively. This information provides valuable insight into the specific activity of ⁶⁴Cu and ⁶⁷Cu.

Using the new apparatus, thermal separation was performed on 43.6 g of irradiated ^natZn, achieving a sublimation efficiency (rate) of 99% and recovering 94% of the zinc in a reusable form. At the end of the thermal separation process, the ⁶⁷Cu yield reached 87%, and subsequent chemical purification resulted in an overall ⁶⁷Cu recovery yield of 79%. Separation experiments for ⁶⁴Cu and ⁶⁷Cu were conducted using neutron irradiated ^natZn of 43.6 g and enriched ⁶⁸Zn of 3.932 g. The sublimation temperature for the irradiated Zn was adjusted to 600°C and 500°C to enhance the Zn sublimation yield while minimizing the co-distillation of copper. Gamma-ray spectrum measured after the purification of the ^natZnO show the dominant γ-ray peaks from the decays of ⁶⁴Cu and ⁶⁷Cu.

The present study demonstrates the fundamental steps for large-scale production of ⁶⁴Cu and ⁶⁷Cu. Deuteron beam intensity of 40 MeV used in this study was approximately 5 μA, 0.1% of 5 mA 40 MeV. As a result of this work, a new project aimed at accelerating 25–40 MeV, 100 µA (20 times the current intensity) deuterons using the existing cyclotron at RARiS, Tohoku University, has been approved (44). This capability is expected to be achieved in the near future.

5 Conclusion

The radionuclide pair ⁶⁴Cu and ⁶⁷Cu is considered an ideal theranostic candidate due to its identical chemical properties, the versatile coordination chemistry of copper, and suitable physical characteristics. Accordingly, radiopharmaceuticals based on ⁶⁴Cu and ⁶⁷Cu are expected to play a key role in the theranostic treatment of various diseases.

A novel method for producing ⁶⁴Cu and ⁶⁷Cu pairs using accelerator neutrons has demonstrated excellent results, enabling the separation and purification of high-quality ⁶⁴Cu and ⁶⁷Cu pairs using the same separation apparatus by sublimation and column chromatography-based separation of ⁶⁴Cu and ⁶⁷Cu from irradiated ⁶⁴Zn and ⁶⁸Zn. The central objective of the newly approved project is to strengthen ongoing research into the domestic production of radiopharmaceuticals containing ⁶⁴Cu and ⁶⁷Cu.

Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Author contributions

YN: Writing – review & editing, Investigation, Writing – original draft, Data curation. MK: Writing – original draft, Investigation, Data curation. HS: Methodology, Data curation, Writing – review & editing. SM: Writing – review & editing, Formal analysis, Methodology, Investigation. KH: Writing – review & editing, Methodology, Investigation. KT: Formal analysis, Data curation, Investigation, Writing – review & editing. AM: Writing – review & editing, Investigation, Methodology. AO: Writing – review & editing, Investigation, Formal analysis. NT: Formal analysis, Writing – review & editing, Investigation. SH: Writing – review & editing, Formal analysis, Writing – original draft, Investigation. MI: Methodology, Investigation, Writing – review & editing. HK: Investigation, Writing – review & editing, Methodology. SF: Writing – review & editing, Conceptualization, Investigation.

Funding

The author(s) declare that financial support was received for the research and/or publication of this article. The present work was supported in part by JSPS KAKENHI Grant Numbers JP19K03903, JP21H03742, JP22K03662, JP23K21830 and in part by Program on Open Innovation Platform with Enterprises, Research Institute and Academia, Japan Science and Technology Agency (JST, OPERA, JPMJOP1721).

Acknowledgments

We thank Kawauchi, Y. and Iwamoto, N. for useful discussions, Watabe, H., Koguchi, Y. for their continuous supports, and the CYRIC cyclotron and electron linac at RARiS at Tohoku University, and the TIARA operating crew in ensuring reliable operation of the instrument.

Conflict of interest

All authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest.

The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

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