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Copper-64 (Cu) is a positron and beta emitting isotope of copper, with applications for molecular radiotherapy and positron emission tomography. Its unusually long half-life (12.7-hours) for a positron-emitting isotope makes it increasingly useful when attached to various ligands, for PET and PET-CT scanning.

Properties

Cu has a half-life of 12.7 hours and decays 17.9% by positron emission to Ni, 39.0% by beta decay to Zn, 43.1% by electron capture to Ni, and 0.475% gamma radiation/internal conversion. These emissions are 0.579 MeV, 0.653 MeV and 1.35 MeV for beta minus, positron, and gamma respectively.

Production

Copper-64 can be produced by several different reactions with the most common methods using either a reactor or a particle accelerator. Thermal neutrons can produce Cu in low specific activity (the number of decays per second per amount of substance) and low yield through the Cu(n,γ)Cu reaction. At the University of Missouri Research Reactor Center (MURR) Cu was produced using high-energy neutrons via the Zn(n,p)Cu nuclear reaction in high specific activity but low yield. Using a biomedical cyclotron the Ni(p,n)Cu nuclear reaction can produce large quantities of the nuclide with high specific activity.

Applications

As a positron emitter, Cu has been used to produce experimental and clinical radiopharmaceuticals for the imaging of a range of conditions. Its beta emissions also raise the possibility of therapeutic applications. Compared to typical PET radionuclides it has a relatively long half-life, which can be advantageous for therapy, and for imaging certain physiological processes.

PET imaging

Bone metastases

Experimental preclinical work has shown that Cu linked to methanephosphonate functional groups has potential as a bone imaging agent.

Neuroendocrine tumors (NETs)

Neuroendocrine tumors (NETs) are localised clinically using a range of DOTA based radiopharmaceuticals. For PET imaging these are typically Gallium-68 based. A commercial Cu-DOTA-TATE product has been FDA approved for localization of somatostatin receptor positive NETs since 2020.

Prostate cancer

The Bombesin peptide has been shown to be overexpressed in BB2 receptors in prostate cancer. CB-TE2A a stable chelation system for Cu was incorporated with Bombesin analogs for in vitro and in vivo studies of prostate cancer. PET-CT imagining studies showed that it underwent uptake into prostate tumor xenografts selectively with decreased uptake into non target tissues. Other preclinical studies have shown that by targeting the gastrin-releasing peptide receptor pancreatic and breast cancer can also be detected.

Renal perfusion

Ethylglyoxal bis(thiosemicarbazone) (ETS) has potential utility as a PET radiopharmaceutical with the various isotopes of copper. Cu-ETS has been used for experimental preclinical myocardial, cerebral and tumor perfusion evaluations, with a linear relationship between the renal uptake and blood flow. Renal perfusion can also be evaluated with CT or MRI instead of PET, but with drawbacks: CT requires administration of potentially allergenic contrast agents. MRI avoids use of ionising radiation but is difficult to implement, and often suffers from motion artefacts. PET with Cu can offer quantitative measurements of renal perfusion.

Wilson’s disease

Wilson disease is a rare condition in which copper is retained excessively in the body. Toxic levels of copper can lead to organ failure and premature death. Cu has been used experimentally to study whole body retention of copper in subjects with this disease. The technique can also separate heterozygous carriers and homozygous normals.

Cancer therapy

Cu-ATSM (diacetyl-bis(N4-methylthiosemicarbazone)) has been shown to increase the survival time of tumor-bearing animals. Areas of low oxygen retention have been shown to be resistant to external beam radiotherapy because hypoxia reduces the lethal effects of ionizing radiation. Cu was believed to kill these cells because of its unique decay properties. In animal models having colorectal tumors with and without induced hypoxia, Cu-ATSM was preferentially taken up by hypoxic cells over normoxic cells. The results demonstrated that this compound increased survival of the tumor bearing hamsters compared with controls.

See also

• Nuclear medicine
• Radioactive tracer
• Radionuclide
• Radiopharmacology

References

1. "Copper, isotope of mass 64". PubChem. National Center for Biotechnology Information. Retrieved 25 April 2021.
2. ^ Bé, M.-M; Chisté, V; Dulieu, C; Mougeot, X; Chechev, V; Kuzmenko, N; Kondev, F; Luca, A; Galán, M; Nichols, A L; Lee, K B; Arinc, A; Pearce, A; Huang, X; Wang, B (2006). "Cu-64" (PDF). In Bé, M.-M (ed.). Table of radionuclides (Volume 6). Sèvres: BIPM. p. 13. ISBN 978-92-822-2242-3.
3. Welch, Michael; Redvanly, Carol S. (2003). Handbook of Radiopharmaceuticals : radiochemistry and applications. New York: Wiley. doi:10.1002/0470846380. ISBN 9780471495604. S2CID 94079329.
4. IAEA (2016). Cyclotron Produced Radionuclides: Emerging Positron Emitters for Medical Applications: 64Cu and 124I. Vienna: International Atomic Energy Agency. ISBN 978-92-0-109615-9.
5. Gutfilen, Bianca; Souza, Sergio AL; Valentini, Gianluca (2 October 2018). "Copper-64: a real theranostic agent". Drug Design, Development and Therapy. 12: 3235–3245. doi:10.2147/DDDT.S170879. PMC 6173185. PMID 30323557.
6. Zhou, Yeye; Li, Jihui; Xu, Xin; Zhao, Man; Zhang, Bin; Deng, Shengming; Wu, Yiwei (1 January 2019). "64 Cu-based Radiopharmaceuticals in Molecular Imaging". Technology in Cancer Research & Treatment. 18: 153303381983075. doi:10.1177/1533033819830758. PMC 6378420. PMID 30764737.
7. Sun, Xiankai; Wuest, Melinda; Kovacs, Zoltan; Sherry, Dean; Motekaitis, Ramunas; Wang, Zheng; Martell, Arthur; Welch, Michael; Anderson, Carolyn (1 January 2003). "In vivo behavior of copper-64-labeled methanephosphonate tetraaza macrocyclic ligands". Journal of Biological Inorganic Chemistry. 8 (1–2): 217–225. doi:10.1007/s00775-002-0408-5. PMID 12459917. S2CID 22225650.
8. "DETECTNET". Drugs@FDA. Food and Drug Administration. Retrieved 25 April 2021.
9. Eychenne, Romain; Bouvry, Christelle; Bourgeois, Mickael; Loyer, Pascal; Benoist, Eric; Lepareur, Nicolas (2 September 2020). "Overview of Radiolabeled Somatostatin Analogs for Cancer Imaging and Therapy". Molecules. 25 (17): 4012. doi:10.3390/molecules25174012. PMC 7504749. PMID 32887456.
10. Parry, Jesse J.; Andrews, Rebecca; Rogers, Buck E. (13 July 2006). "MicroPET Imaging of Breast Cancer Using Radiolabeled Bombesin Analogs Targeting the Gastrin-releasing Peptide Receptor". Breast Cancer Research and Treatment. 101 (2): 175–183. doi:10.1007/s10549-006-9287-8. PMID 16838112. S2CID 25579379.
11. Green, Mark A.; Mathias, Carla J.; Willis, Lynn R.; Handa, Rajash K.; Lacy, Jeffrey L.; Miller, Michael A.; Hutchins, Gary D. (April 2007). "Assessment of Cu-ETS2 as a PET radiopharmaceutical for evaluation of regional renal perfusion". Nuclear Medicine and Biology. 34 (3): 247–255. doi:10.1016/j.nucmedbio.2007.01.002. PMID 17383574.
12. Welch, Michael J.; Redvanly, Carol S. (2003). Handbook of Radiopharmaceuticals: Radiochemistry and Applications. John Wiley & Sons. p. 407. ISBN 978-0-471-49560-4.
13. Reed, Emily; Lutsenko, Svetlana; Bandmann, Oliver (2018). "Animal models of Wilson disease". Journal of Neurochemistry. 146 (4): 356–373. doi:10.1111/jnc.14323. PMC 6107386. PMID 29473169.
14. Lewis, J. S.; Laforest, R.; Buettner, T. L.; Song, S.-K.; Fujibayashi, Y.; Connett, J. M.; Welch, M. J. (30 January 2001). "Copper-64-diacetyl-bis(N4-methylthiosemicarbazone): An agent for radiotherapy". Proceedings of the National Academy of Sciences. 98 (3): 1206–1211. Bibcode:2001PNAS...98.1206L. doi:10.1073/pnas.98.3.1206. PMC 14733. PMID 11158618.

• Isotopes of copper
• Positron emitters
• Medical isotopes