Theragnostic 64Cu/67Cu Radioisotopes Production With RFT-30 Cyclotron

⁶⁴Cu and ⁶⁷Cu are theragnostic pair radionuclides with promising application in the nuclear medicine. ⁶⁴Cu is PET nuclide for the non-invasive diagnosis and ⁶⁷Cu is beta emitter for therapy of various cancers. This study discusses optimization efforts in the production of these radioactive coppers carried out with 30 MeV cyclotron. Optimized conditions include target preparation, chemical separation, and quality control. The production routes of ⁶⁴Cu and ⁶⁷Cu were studied based on the nuclear reactions of ⁶⁴Ni(p,n)⁶⁴Cu and ⁷⁰Zn(p,α)⁶⁷Cu. The produced ⁶⁴Cu and ⁶⁷Cu have >99.9% of the radionuclidic purity. The yield at the end of bombardment (EOB) of ⁶⁴Cu and ⁶⁷Cu is 28.5 MBq/μAh and ⁶⁷Cu is 0.58 MBq/μAh, respectively.

Introduction

The nuclear medicine field relies on incorporating radioisotopes in small-molecule, nucleic acids, peptides, proteins, antibodies, and drug delivery technologies (1–3) that show high sensitivity for various diseases in order to impart diagnostic and therapeutic effects. Because of the same chemical properties, Copper-64 (⁶⁴Cu) and (Copper-67) ⁶⁷Cu can form chemical complexes using the identical labeling protocol, and diagnosis/therapy can be performed simultaneously (4–8). Copper is an essential trace element for the health of all living creatures. In humans, copper is necessary for proper function of organs and metabolic processes (9–13). Therefore, radioactive copper is a promising candidate that can be applied to various diseases. The multipurpose coordination chemistry of copper allows for its radiometallation with various chelators, such as DOTA (1,4,7,10-tetraazacyclododecane-tetraacetic acid), NOTA (1,4,7-triazacyclononane-triacetic acid), TETA (1,4,8,11-tetraazacyclotetraadecane-1,4,8,11-tetraacetic acid), and CB-TE2A (4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2] hexadecane) (14–17), which can be conjugated to various radiopharmaceuticals. ⁶⁴Cu(T_1/2: 12.7 h) is an attractive radioisotope of significant interest for positron emission tomography (PET) with β⁺(E_max: 653.03 keV and E_mean: 278.21 keV) and EC (electron capture: 1675.03 and 1345.77 keV) (18, 19). Furthermore, it has a relatively long half-life compared to fluorine-18 (T_1/2: 110 min) and carbon-11 (T_1/2: 20.4 min) (19, 20), which corresponds to an adequate half-life for drug requiring long-term follow-up. ⁶⁷Cu(T_1/2 = 61.83 h, β⁻ mean energy = 141 keV) is a radioisotope with significant potential for therapeutic applications in nuclear medicine due to a similar beta mean energy as 134 keV of ¹⁷⁷Lu (21–24, 26). Despite its potential, the use of ⁶⁷Cu for radionuclide therapy has been hindered for decades by its limited supply and low-specific activity. However, the production of ⁶⁷Cu has been attempted through various nuclear reactions, such as ⁶⁸Zn(p,2p)⁶⁷Cu, ⁷⁰Zn(p,α)⁶⁷Cu, ⁶⁷Zn(n,p)⁶⁷Cu, and ⁶⁸Zn(γ,p)⁶⁷Cu (25– 31). In this study, the irradiation, target preparation, chemical separation, and quality control of radioactive copper (⁶⁴Cu and ⁶⁷Cu) were verified. The results show that optimized enriched target electrodeposition, proton beam irradiation, separation/purification, and quality control processes can enhance the routine capability of ⁶⁴Cu and ⁶⁷Cu production.

Materials and Methods

As shown in Figure 1 below, radioisotopes are produced with a proton beam irradiation process to ⁶⁴Ni and ⁷⁰Zn electrodeposited target. In order to maximize the target cooling and the production efficiency of ⁶⁴Cu and ⁶⁷Cu when irradiating the target material with a proton beam, a tilted target and a backside water cooling system were applied. The radioactive copper from the target materials was carried out through a solid-phase separation method. The steps of impurities removal, radioactive copper purification, and target material recovery were performed. Finally, ⁶⁴Cu and ⁶⁷Cu were verified through quality control of radionuclidic purity and impurity metal content.

FIGURE 1

Figure 1. Schematic illustration of pair-radioisotope production route.

Materials and Reagents

Ultra-high purity reagents were used for production of ⁶⁴Cu and ⁶⁷Cu in this study. Isotopically enriched ⁶⁴Ni (⁵⁸Ni: 0.05%, ⁶⁰Ni: 0.03%, ⁶¹Ni: 0.004%, ⁶²Ni: 0.396%, ⁶⁴Ni: 99.52%) and ⁷⁰Zn (⁶⁴Zn: 0.1%, ⁶⁶Zn: 0.1%, ⁶⁷Zn: 0.1%, ⁶⁸Zn: 2.2%, ⁷⁰Zn: 97.5%) were supplied from ISOFLEX (San Francisco, CA, USA). The proton beam verification film (Gafchromic Quick Phantom) was obtained from Ashland Company (Gafchromic^TM Ashland Inc., New Jersey, USA). Substrates of Au-Cu and Ag were received from Doowon Machinery Company (Seoul, South Korea) in a bar shape (1 x 12 cm). Concentrated HCl was purchased from Thermo Fisher Scientific (Waltham, MA, USA); Hydrazine hydrate and sodium hydroxide were purchased from Sigma-Aldrich (St. Louis, MO, USA); CU resin and ZR cartridge were obtained from TRISKEM Company (Bruz, Brittany, France); and AG1X8 anion exchange resin was obtained from Bio-Rad Laboratories (Hercules, CA, USA).

Equipment

The proton beam irradiation studies were performed using a RFT-30 cyclotron (30 MeV, Korea Atomic Energy Research Institute). The apparatus for enriched target material electroplating and dissolution was developed in house. For ⁶⁴Cu and ⁶⁷Cu radioactivity measurement, an ionization chamber (AtomlabTM500, BIODEX, New York, USA) was used. The radionuclidic purity was measured by a calibrated high purity germanium gamma detector (HPGe, Oak Ridge, USA). An inductively coupled plasma-mass spectrometry (ICP-MS) system (Agilent 7500, Stevens Creek Blvd, CA, USA) was used to analyze the metallic impurity of the final eluted radioactive copper solution.

Target Preparation

The electroplated target was prepared by an electrodeposition procedure. A typical electroplating target material (⁶⁴Ni or ⁷⁰Zn) was dissolved in 10 mL of concentrated HCl. After the target metal was completely dissolved, the target solution was then evaporated to dryness under a vacuum system. The residue was re-dissolved in 600 mL of water, and then 2 mL of hydrazine hydrate was added as an electrolyte to the target solution. The final solution was loaded into the electroplating cell with the substrate. The electroplating was carried out on the substrate at optimized conditions (waveform: square, frequency: 50 Hz, amplitude: 2000, tau: 2, phase: 10 deg, chopping frequency and duty: 100 Hz and 84%, square duty: 60%). After electroplating, the ⁶⁴Ni and ⁷⁰Zn targets were examined by measuring their thickness and uniformity.

Proton Beam Irradiation

⁶⁴Cu and ⁶⁷Cu were produced at RFT-30 MeV cyclotron by ⁶⁴Ni(p,n)⁶⁴Cu and ⁷⁰Zn(p,α)⁶⁷Cu nuclear reaction, respectively. The electroplated target was fixed on the solid target station and irradiated with 11.0 MeV (⁶⁴Cu) and 17.7 MeV (⁶⁷Cu) protons. The solid target station was fitted with a self-made cradle for the tilted 6° target compared to the beam line. Using Gafchromic film, we optimized the target area of 1175 mm² with a beam distribution of 90% under the same conditions as employed for ⁶⁴Cu and ⁶⁷Cu. Furthermore, the beam currents and cooling system were considered for reducing target thermal damage. The central cooling-water system was connected to the target station (water-pressure: 1.1 MPa, water cooling line: 1/4”). For the production of ⁶⁴Cu and ⁶⁷Cu, the beam current was fixed at 30 and 100 μA for 3 and 12 h, respectively.

Separation and Purification

Copper-64

The irradiated ⁶⁴Ni target (Electroplated target weight: 130 mg) was directly transported to the hot-cell using an automatic target transport system. The irradiated target was dissolved in 7 mL of 8 M HCl with a target dissolving device at 90°C for 1.5 h. The recovered target solution was filtered with a 0.45 μm PVDF syringe filter. To adjust the pH of the dissolved target solution to 2, the solution was evaporated and re-dissolved with water. ⁶⁴Cu was separated using copper selective CU resin. In brief, 300 mg of CU resin was immersed in water to remove air bubbles and then left in a vacuum for 30 min at 8 mbar. In the wet-packing method, the empty column was filled with immersed CU resin and then the solution was replaced with 0.01 M HCl for the pre-conditioning column. The proton beam irradiated crude ⁶⁴Ni target solution was loaded on the CU resin pre-packed column at a concentration of 0.01 M HCl. After loading the ⁶⁴Cu and other radio impurities, the CU resin was washed with 20 mL of 0.01 M HCl (1.0 mL/min) to recover and remove the ⁶⁴Ni target and impurities. Finally, the ⁶⁴Cu was eluted with 2 mL of 8 M HCl, and then ⁶⁴Cu fractions were collected and then evaporated nearly to dryness under a vacuum system.

Copper-67

The separation and purification of the carrier-free ⁶⁷Cu were performed as follows. After irradiation, the ⁷⁰Zn target (electroplated target weight: 260 mg) was placed into the target dissolving device. The ⁷⁰Zn target was dissolved in 7 mL of 9 M HCl at 90°C for 10 min. The dissolved target solution was filtered with a 0.45 μm PVDF syringe filter. We used a two-step separation procedure to remove ⁶⁶Ga impurities and recover the ⁷⁰Zn target materials with a ZR cartridge and AG1X8 ion exchange resin. In brief, the target solution was loaded into a ZR cartridge to remove ⁶⁶Ga and then the cartridge was washed with 9 M HCl for complete recovery of ⁷⁰Zn and ⁶⁷Cu. The eluted solution was passed through a wet-packed AG1X8 column (packing height: 7 cm). The column was then washed with 2.5 column volumes of 9 M HCl to eliminate other impurities. The ⁶⁷Cu was eluted with 8 mL of 2 M HCl, and then ⁶⁷Cu fractions were collected and then evaporated nearly to dryness under a vacuum system. Finally, enriched ⁷⁰Zn was completely recovered with 30 mL of 2 M HNO₃ and then evaporated for future use.

Quality Control

Metallic Impurity

The impurity metal content (V, Cr, Mn, Fe, Co, Ni, and Zn) of the separated and purified radioactive copper (⁶⁴Cu and ⁶⁷Cu) was evaluated via an inductively coupled plasma-mass spectrometer (ICP-MS) to secure biological safety and optimize the radio-labeling yield. The operating conditions were as follows: instrument (Agilent 7500 series), nebulizer (Babington type), spray-chamber (Scott-type), FR generator (frequency: 10 MHz, power 1,300 W), Ar flow rate (plasma 15 L/min, auxiliary 0.9 L/min, nebulizer 1 L/min), sample uptake rate 1 mL/min, and number of replicates (three).

Radionuclidic Purity

Radionuclidic purity was determined using gamma spectroscopy with a high purity germanium detector, multichannel analyzer, and Gamma Vision software. Efficiency and energy calibration was performed with ²¹⁰Pb (401 Bq/g; 57 keV), ²⁴¹Am (40 Bq/g; 60 keV), ¹⁰⁹Cd (385 Bq/g; 88 keV), ⁵⁷Co (15 Bq/g; 122 keV), ^123mTe (22 Bq/g; 159 keV), ⁵¹Cr (491 Bq/g; 320 keV), ¹¹³Sn (73 Bq/g; 392 keV), ⁸⁵Sr (92 Bq/g; 514 keV), ¹³⁷Cs (65 Bq/g; 662 keV), ⁸⁸Y (149 Bq/g; 898 and 1,836 keV), and ⁶⁰Co (77 Bq/g; 1,173 and 1,333 keV). Activity of the multi-nuclide standard source was checked at the day of measurement. The purified samples were fixed on a universal sample holder located 5 cm from the detector window. The gamma spectra were recorded for 86,400 s each for the crude target solution and purified product.

Results

Target Manufacturing

To optimize the production of ⁶⁴Cu and ⁶⁷Cu via the nuclear reaction of ⁶⁴Ni(p,n)⁶⁴Cu and ⁷⁰Zn(p,α)⁶⁷Cu, we prepared ⁶⁴Ni and ⁷⁰Zn targets on the substrate by electrodeposition. Gold and silver were used as a cathode and a platinum rod was used as an anode. The bar-shaped substrates were electrodeposited with ⁶⁴Ni and ⁷⁰Zn. After cleaning and drying, the weight of the electroplated ⁶⁴Ni and ⁷⁰Zn on the substrate was 130 and 260 mg, respectively. The target having a uniform surface was confirmed through an optical microscope (Figure 2; Supplementary Figure 4).

FIGURE 2

Figure 2. Enriched target electroplated onto substrate (Au-Cu and Ag) (A) ⁶⁴Ni electrodeposition with Au-Cu substrate (B) ⁷⁰Zn electrodeposition with silver substrate (magnification under optical microscope X20).

Proton Beam Irradiation

Enriched ⁶⁴Ni and ⁷⁰Zn targets were mounted using a self-produced cradle (6° tilted target system) and a target transfer device and then a proton beam was irradiated at 11 and 17.7 MeV incident energy, respectively. We predicted the nuclear reaction cross-section for ⁶⁴Cu and ⁶⁷Cu production as 800 and 15 mb at 11 and 17.7 MeV incident energies, respectively, through the NNDC (National nuclear data center) database. The nuclear cross-sections of ⁶⁴Cu and ⁶⁷Cu are detailed in the Supplementary Figures 1–5. Based on the theoretical calculation results, the proton beam was irradiated with accumulated current of 90 and 1,200 μAh. The purified ⁶⁴Cu and ⁶⁷Cu were produced and isolated from irradiated ⁶⁴Ni and ⁷⁰Zn targets; considering the correction due to the decay, at the end of bombardment (EOB) we obtained ⁶⁴Cu 28.5 MBq/μAh and ⁶⁷Cu 0.58 MBq/μAh.

Separation and Purification

Preparation of ⁶⁴Cu

After irradiation for three hours, the ⁶⁴Cu was completely separated from the enriched ⁶⁴Ni target solution (Figure 3A). Figure 4A shows the elution profile obtained from the measurement of the fraction activity from the CU resin. To elute ⁶⁴Cu from CU resin, ⁶⁴Cu was eluted four times with a volume of 500 μL at a flow rate of 0.5 mL/min using 8 M HCl (⁶⁴Cu elution yield: 98.6%). The radioactivity of purified ⁶⁴Cu in each 500 μL fraction and the residual activity on the column were measured by using a dose calibrator. To improve the availability of ⁶⁴Cu in mild labeling conditions, the purified ⁶⁴Cu solution was evaporated and re-dissolved in 0.1 M HCl. Finally, ⁶⁴Ni was collected during the separation and purification procedure for the target recycling.

FIGURE 3

Figure 3. (A,B) Schematic of chemical separation processing.

FIGURE 4

Figure 4. Elution profile of radioactive copper separation from the irradiated target materials (A) ⁶⁴Cu and (B) ⁶⁷Cu.

Preparation of ⁶⁷Cu

After irradiation for 12 h, the enriched ⁷⁰Zn target was completely dissolved in 9 M HCl. The target solution was chemically processed using two-step separation with a solid-phase resin, specifically, a ZR cartridge and AG1X8 resin (Figure 3B). The target solution was passed through the ZR cartridge to remove ⁶⁶Ga radio metallic impurities. The ⁶⁶Ga was completely removed from the crude target solution and then fractions were collected for subsequent separation. During ⁶⁷Cu production, ~2 days of cooling time was required to remove ⁶⁶Ga. To maximize the production yield, the method of removing ⁶⁶Ga was adopted within 20 minutes. Figure 4B shows the elution profile obtained from the measurement of fraction activity from the collected solution. AG1-X8 ion exchange resin was c in water and transferred into an empty column (1 x 10 cm). The target solution was passed through pre-conditioned AG1X8 resin. To elute ⁶⁷Cu and ⁷⁰Zn from the AG1X8 resin, 2 M HCl and 2 M HNO₃ were used at a 1.0 mL/min flow rate, respectively.

Quality Control

The radionuclidic purity of ⁶⁴Cu and ⁶⁷Cu in the separated fraction volume was assessed using a high purity germanium detector. The radioisotope production routes involved radionuclidic impurities that should be removed by chemical separation before use. The gamma energy of the final product must be measured. Figure 5A shows >99% high purity γ-ray spectra of purified ⁶⁴Cu and ⁶⁷Cu. In addition, gamma energy spectra of proton beam irradiated target materials described in the Supplementary Figures 1–5. Metallic impurities of the ⁶⁴Cu and ⁶⁷Cu elute were determined using ICP-MS to identify metal species that may compete with copper during radio-labeling reactions for radiopharmaceuticals. The content of metallic impurities in the purified ⁶⁴Cu and ⁶⁷Cu is <1 ppm, as shown in Figure 5B, and it will not affect the radio-labeling reaction (Supplementary Figure 5).

FIGURE 5

Figure 5. Quality control of pair-radioisotopes (A) gamma energy spectrum of purified ⁶⁴Cu (left) and ⁶⁷Cu (right), (B) metallic impurity content in purified final volume of ⁶⁴Cu (left) and ⁶⁷Cu (right).

Discussion and Conclusions

The production procedure of pair-radioisotope ⁶⁴Cu and ⁶⁷Cu has been studied. This attempt is an imperative study to guarantee the supply and quality of radioisotopes for diagnosis/therapy in the field of nuclear medicine. Each condition was established using RFT-30 cyclotron, equipment, and chemicals to optimize the entire process, including proton beam irradiation, targetry, chemical separation, and quality control of ⁶⁴Cu and ⁶⁷Cu. The expected thick target yields of ⁶⁴Cu and ⁶⁷Cu were calculated considering the NNDC cross-sections with 11 and 17.7 MeV as incident energy, respectively. The obtained experimental production yields were 2.57 GBq and 696 MBq, respectively. These results have secured sufficiently radioactivity that can be supplied to researchers in the field of nuclear medicine. Furthermore, we will continue to conduct research for mass production. Preparation of electrodeposited target has several advantages including high solidity, density, and heat dissipation efficiency for beam irradiation. Moreover, it is helpful for tilted targets to secure the maximum beam irradiation area. Chemical separation studies were performed using ZR cartridge and AG1X8 resin for ⁶⁷Cu and CU resin for ⁶⁴Cu, respectively, considering the copper adsorption capacity, target material recovery, and impurity removal. ⁶⁴Cu and ⁶⁷Cu were prepared with >98% separation efficiency, and the final product contains the maximum radioactivity in the minimum volume to introduce the radioactive copper in the radiopharmaceutical under mild reaction conditions, it was evaporated and dried and then re-dissolved in 0.1 M HCl. Furthermore, the radiopharmaceuticals limit the amount of radionuclide contamination allowed in ⁶⁴Cu and ⁶⁷Cu solutions for safety and radio-labeling efficiency. The major radionuclide contaminant of radioactive copper solutions is its target material, such as nickel or zinc. Through the quality control procedure, the radionuclidic purity of the final eluted solution was measured as >99% and the metallic impurity content was maintained less than 1 ppm. Further studies on the automation separating apparatus are underway for ⁶⁴Cu and ⁶⁷Cu production.

Data Availability Statement

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

Author Contributions

JYL and JC: conceptualization, data curation, formal analysis, methodology, visualization, writing—original draft, and investigation. JP: funding acquisition and project administration. MH, SY, YK, JL, and JJ: cyclotron operating. JP and SY: validation and writing—review and editing. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by the Nuclear R&D Program through the National Research Foundation of Korea, funded by the Ministry of Science, ICT, and Future Planning (2017M2A2A6A05016600 and 2021M2E7A1079112) and NTIS (1711123216), Republic of Korea.

Conflict of Interest

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

Publisher's Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary Material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmed.2022.889640/full#supplementary-material

References

1. Man F, Gawne PJ, de Rosales RT. Nuclear imaging of liposomal drug delivery systems: a critical review of radiolabelling methods and applications in nanomedicine. Adv Drug Deliv Rev. (2019) 143:134–60. doi: 10.1016/j.addr.2019.05.012

PubMed Abstract | CrossRef Full Text | Google Scholar

2. Peltek OO, Muslimov AR, Zyuzin MV, Timin AS. Current outlook on radionuclide delivery systems: from design consideration to translation into clinics. J Nanobiotechnology. (2019) 17:1–34. doi: 10.1186/s12951-019-0524-9

PubMed Abstract | CrossRef Full Text | Google Scholar

3. Witney TH, Blower PJ. The chemical tool-kit for molecular imaging with radionuclides in the age of targeted and immune therapy. Cancer Imaging. (2021) 21:1–14. doi: 10.1186/s40644-021-00385-8

PubMed Abstract | CrossRef Full Text | Google Scholar

4. Ferreira CA, Ehlerding EB, Rosenkrans ZT, Jiang D, Sun T, Aluicio-Sarduy E, et al. ^86/90Y-Labeled monoclonal antibody targeting tissue factor for pancreatic cancer theranostics. Mol Pharm. (2020) 17:1697–705. doi: 10.1021/acs.molpharmaceut.0c00127

PubMed Abstract | CrossRef Full Text | Google Scholar

5. McNeil BL, Robertson AK, Fu W, Yang H, Hoehr C, Ramogida CF, et al. Production, purification, and radiolabeling of the ²⁰³Pb/²¹²Pb theranostic pair. EJNMMI Radiopharm Chem. (2021) 6:1–18. doi: 10.1186/s41181-021-00121-4

PubMed Abstract | CrossRef Full Text | Google Scholar

6. Qaim SM, Scholten B, Neumaier B. New developments in the production of theranostic pairs of radionuclides. J Radioanal Nucl Chem. (2018) 318:1493–509. doi: 10.1007/s10967-018-6238-x

CrossRef Full Text | Google Scholar

7. Cho EH, Lim JC, Lee SY, Park UJ. ^44/47Scandium labelled cholecystokinin derivative for cancer theragnostics. Oncol Radiother. (2021) 16:1–5. doi: 10.21203/rs.3.rs-992450/v1

CrossRef Full Text | Google Scholar

8. Earley DF, Flores JE, Guillou A, Holland JP. Photoactivatable bis (Thiosemicarbazone) derivatives for copper-64 radiotracer synthesis. Dalton Trans. (2022) 51:5041–52. doi: 10.1039/D2DT00209D

PubMed Abstract | CrossRef Full Text | Google Scholar

9. Chen J, Jiang Y, Shi H, Peng Y, Fan X, Li C. The molecular mechanisms of copper metabolism and its roles in human diseases. Pflügers Arch Eur J Physiol. (2020) 472:1415–29. doi: 10.1007/s00424-020-02412-2

PubMed Abstract | CrossRef Full Text | Google Scholar

10. Gromadzka G, Tarnacka B, Flaga A, Adamczyk A. Copper dyshomeostasis in neurodegenerative diseases—therapeutic implications. Int J Mol Sci. (2020) 21:9259. doi: 10.3390/ijms21239259

PubMed Abstract | CrossRef Full Text | Google Scholar

11. Latorre M, Troncoso R, Uauy R. Biological aspects of copper. In: Kerkar N, Roberts EA. Clinical and Translational Perspectives on Wilson Disease. Elsevier (2019). p. 25–31. doi: 10.1016/B978-0-12-810532-0.00004-5

CrossRef Full Text | Google Scholar

12. Mustafa SK, AlSharif MA. Copper (Cu) an essential redox-active transition metal in living system—a review article. Am J Anal Chem. (2018) 9:15. doi: 10.4236/ajac.2018.91002

CrossRef Full Text | Google Scholar

13. Shanbhag VC, Gudekar N, Jasmer K, Papageorgiou C, Singh K, Petris MJ. Copper metabolism as a unique vulnerability in cancer. Biochimica et Biophysica Acta Mol Cell Res. (2021) 1868:118893. doi: 10.1016/j.bbamcr.2020.118893

PubMed Abstract | CrossRef Full Text | Google Scholar

14. Yang H, Gao F, McNeil B, Zhang C, Yuan Z, Zeisler S, et al. Synthesis of dota-pyridine chelates for ⁶⁴Cu coordination and radiolabeling of αmsh peptide. EJNMMI Radiopharm Chem. (2021) 6:1–16. doi: 10.1186/s41181-020-00119-4

PubMed Abstract | CrossRef Full Text | Google Scholar

15. Khosravifarsani M, Ait-Mohand S, Paquette B, Sanche L, Guérin B. High cytotoxic effect by combining copper-64 with a nota–terpyridine platinum conjugate. J Med Chem. (2021) 64:6765–76. doi: 10.1021/acs.jmedchem.1c00039

PubMed Abstract | CrossRef Full Text | Google Scholar

16. Zhu X, Miao X, Qin X, Zhu X. Design of Immunogens: The effect of bifunctional chelator on immunological response to chelated copper. J Pharm Biomed Anal. (2019) 174:263–9. doi: 10.1016/j.jpba.2019.06.001

PubMed Abstract | CrossRef Full Text | Google Scholar

17. Ocak M, Beaino W, White A, Zeng D, Cai Z, Anderson CJ. ⁶⁴Cu-labeled phosphonate cross-bridged chelator conjugates of C (Rgdyk) for Pet/Ct imaging of osteolytic bone metastases. Cancer Biother Radiopharm. (2018) 33:74–83. doi: 10.1089/cbr.2017.2419

PubMed Abstract | CrossRef Full Text | Google Scholar

18. Pettersen NIJ. Novel Production Pathways for the ^{64, 67}Cu Theranostic Pair: Cross Section Measurements for the ^NatZn (N, X) ^{64, 67}Cu Reactions. (2020).

Google Scholar

19. National Nuclear Data Center Brookhaven National Laboratory. (2008). Available online at: https://www.nndc.bnl.gov/nudat2/

20. Welch MJ, Kilbourn MR, Green MA. Radiopharmaceuticals labeled with short-lived positron-emitting radionuclides. Radioisotopes. (1985) 34:170–9. doi: 10.3769/radioisotopes.34.3_170

PubMed Abstract | CrossRef Full Text | Google Scholar

21. Yano S, Haba H, Shibata S, Komori Y, Takahashi K, Wakitani Y, et al. Specification of ⁶⁷Cu Produced in the ⁷⁰Zn (d, αn)⁶⁷ Cu Reaction.

Google Scholar

22. Hao G, Mastren T, Silvers W, Hassan G, Öz OK, Sun X. Copper-67 radioimmunotheranostics for simultaneous immunotherapy and immuno-spect. Sci Rep. (2021) 11:1–11. doi: 10.1038/s41598-021-82812-1

PubMed Abstract | CrossRef Full Text | Google Scholar

23. Ohya T, Nagatsu K, Suzuki H, Fukada M, Minegishi K, Hanyu M, et al. Small-scale production of ⁶⁷Cu for a preclinical study via the ⁶⁴Ni(α,p)⁶⁷Cu channel. Nucl Med Biol. (2018) 59:56–60. doi: 10.1016/j.nucmedbio.2018.01.002

PubMed Abstract | CrossRef Full Text | Google Scholar

24. Parrilha GL, dos Santos RG, Beraldo H. Applications of radiocomplexes with thiosemicarbazones and bis (Thiosemicarbazones) in diagnostic and therapeutic nuclear medicine. Coord Chem Rev. (2022) 458:214418. doi: 10.1016/j.ccr.2022.214418

CrossRef Full Text | Google Scholar

25. Gopalakrishna A, Suryanarayana SV, Naik H, Dixit TS, Nayak BK, Kumar A, et al. Production, separation and supply prospects of ⁶⁷Cu with the development of fast neutron sources and photonuclear technology. Radiochimica Acta. (2018) 106:549–57. doi: 10.1515/ract-2017-2847

CrossRef Full Text | Google Scholar

26. Jalilian AR, Gizawy MA, Alliot C, Takacs S, Chakarborty S, Rovais MR, et al. Iaea Activities on ⁶⁷Cu, ¹⁸⁶Re, ⁴⁷Sc theranostic radionuclides and radiopharmaceuticals. Curr Radiopharm. (2021) 14:306–14. doi: 10.2174/1874471013999200928162322

PubMed Abstract | CrossRef Full Text | Google Scholar

27. Pupillo G, Mou L, Martini P, Pasquali M, Boschi A, Cicoria G, et al. Production of ⁶⁷Cu by enriched ⁷⁰Zn targets: first measurements of formation cross sections of ⁶⁷Cu, ⁶⁴Cu, ⁶⁷Ga, ⁶⁶Ga, ^69mZn and ⁶⁵Zn in interactions of ⁷⁰Zn with protons above 45 Mev. Radiochimica Acta. (2020) 108:593–602. doi: 10.1515/ract-2019-3199

CrossRef Full Text | Google Scholar

28. Qaim SM, Hussain M, Spahn I, Neumaier B. Continuing nuclear data research for production of accelerator-based novel radionuclides for medical use: a mini-review. Front Phys. (2021):16:639290. doi: 10.3389/fphy.2021.639290

CrossRef Full Text | Google Scholar

29. Medvedev DG, Mausner LF, Meinken GE, Kurczak SO, Schnakenberg H, Dodge CJ, et al. Development of a large scale production of ⁶⁷Cu from ⁶⁸Zn at the high energy proton accelerator: closing the ⁶⁸Zn cycle. Appl Radiat Isotopes. (2012) 70:423–9. doi: 10.1016/j.apradiso.2011.10.007

PubMed Abstract | CrossRef Full Text | Google Scholar

30. Nigron E, Guertin A, Haddad F, Sounalet T. Is ⁷⁰Zn(D, X)⁶⁷Cu the best way to produce ⁶⁷Cu for medical applications? Front Med. (2021) 8:1059. doi: 10.3389/fmed.2021.674617

PubMed Abstract | CrossRef Full Text | Google Scholar

31. Merrick MJ, Rotsch DA, Tiwari A, Nolen J, Brossard T, Song J, et al. Imaging and dosimetric characteristics of ⁶⁷Cu. Phys Med Biol. (2021) 66:035002. doi: 10.1088/1361-6560/abca52

PubMed Abstract | CrossRef Full Text | Google Scholar