Copper-64

Copper-64, ⁶⁴Cu
General
Symbol	64Cu
Names	copper-64, Cu-64
	Isotopes of copper ; Complete table of nuclides

Copper-64 (⁶⁴Cu) is a positron emitting isotope of copper, with applications for molecular radiotherapy and positron emission tomography.

Properties

⁶⁴Cu has a half-life of 12.701 ± 0.002 hours and decays by 17.86 (± 0.14)% by positron emission to ⁶⁴Ni, 39.0 (± 0.3)% by beta decay to ⁶⁴Zn, 43.075 (± 0.500)% by electron capture to ⁶⁴Ni, and 0.475 (± 0.010)% gamma radiation/internal conversion. These emissions are 0.5787 (± 0.0009) and 0.6531 (± 0.0002) MeV for beta minus and positron respectively and 1.34577 (± 0.00016) MeV for gamma.[1]

The main oxidation states of copper are I and II since Cu³⁺ is too powerful to exist in biochemical systems. Furthermore, copper(I) exists as a strong complex in aqueous solution and is not often seen. Copper(II) forms mononuclear complexes that are paramagnetic and prefers ligands of sulfur and nitrogen.[2]

Copper is essential in the human body as both a catalyst and as part of enzymes. Copper is mainly involved in redox reactions throughout the body, but also plays a role in iron transportation in blood plasma.

Production

Copper-64 can be technically reproduced by several different reactions with the most common methods using either a reactor or an accelerator. Thermal neutrons can produce ⁶⁴Cu in low specific activity (the number of decays per second per amount of substance) and low yield through the ⁶³Cu(n,γ)⁶⁴Cu reaction. At the University of Missouri Research Reactor Center (MURR) ⁶⁴Cu was produced using high-energy neutrons via the ⁶⁴Zn(n,p)⁶⁴Cu reaction in high specific activity but low yield. Using a biomedical cyclotron the ⁶⁴Ni(p,n)⁶⁴Cu nuclear reaction can produce large quantities of the nuclide with high specific activity.[2]

Applications

Wilson’s disease

Wilson's 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. ⁶⁴Cu is used to study whole body retention of copper in subjects with this disease. The technique can also separate heterozygous carriers and homozygous normals.

Assessment of renal perfusion with Cu-ETS

Ethylglyoxal bis (thiosemicarbazone) has potential utility as a PET radiopharmaceutical with the various isotopes of copper. ⁶⁴Cu-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 toxic contrast agents, and if repeated scans are required, CT will expose the patient to even more ionizing radiation. MRI avoids this radiation but is difficult to implement, and often suffers from motion artifacts. Thus, PET scans utilizing copper isotopes offer quantitative measurements and are suitable for use in regional renal perfusion assessments.[3][4]

Dissociation of copper from bifunctional chelates

The in vivo metabolism of bifunctional chelates is important for optimal targeting of specific organs or tumors. ⁶⁴Cu TETA-Octreotide is a chelate that has been shown to bind to the somatostatin receptor. This in turn inhibited the growth of somatostatin-receptor positive tumors in rats. This compound however showed activity in blood, liver and bone marrow. Whether the chelate dissociated and resulted in ⁶⁴Cu binding to the protein superoxide dismutase (SOD) in rat liver was investigated by utilizing a gel electrophoresis assay for the detection of SOD. It was shown that ⁶⁴Cu did in fact dissociate from the TETA chelator and bound to SOD, and to a lesser extent, other proteins. This is caused either because chelate-biomolecules are not thermodynamically stable or are not kinetically stable. Kinetic stability is more central in the determination of in vivo stability than thermodynamic stability however. To prevent this unwanted dissociation, molecules of higher stability are needed.[5]

Investigating methanephosphonate tetraaza macrocyclic ligands

Three different compounds of tetraazacyclododecane ligands with methanephosphonate functional groups were synthesized and tested for their in vivo stability. These were all labeled with ⁶⁴Cu and then studied for their biodistribution in rat organs (liver, kidney, blood and bone). ⁶⁴Cu-DO2P demonstrated the most efficient clearance through the blood, liver and kidney of all the ligands tested and had similar uptake and clearance in those organs as did Cu-TETA. The ⁶⁴Cu-DO2P ligand had the highest in vivo stability and thus makes it a strong candidate for copper radiopharmaceuticals.[6]

Investigating cross-bridged tetraaza ligands

To better understand the in vivo stability of peptide conjugated CB-TE2A and Cu-TETA, cross-bridged monoamides were synthesized and tested for their biodistribution. CB-TEAMA, CB-MeTEAMA and CB-PhTEAMA were all produced. Retention in nontarget tissues such as the liver make full characterization of the peptide difficult, so molecules which clear those organs are necessary. The results showed that CB-TE2A did in fact have good biodistribution and in vivo stability as well as all cross-bridged complexes. Thus, this is evidence in favor of CB-TE2A as a bifunctional chelator without additional modification.[7]

Cancer detection with bombesin analogs

The Bombesin peptide has been shown to be overexpressed in BB2 receptors in prostate cancer. CB-TE2A a stable chelation system for ⁶⁴Cu 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 studies have shown that by targeting the gastrin-releasing peptide receptor pancreatic and breast cancer can be detected with PET imagining.[8]

Cancer therapy

⁶⁴Cu-ATSM – copper(II) (diacetyl-bis (N4-methylthiosemicarbazone)) – is being studied as a possible cancer therapy.

⁶⁴Cu-ATSM (diacetyl-bis(N4-methylthiosemicarbazone)) has been shown to increase the survival time of tumor-bearing animals with no acute toxicity. Areas of low oxygen retention have been shown to be resistant to radiotherapy because hypoxia reduces the lethal effects of ionizing radiation. ⁶⁴Cu was believed to kill these cells because of its unique decay properties. In this experiment, animal models having colorectal tumors with and without induced hypoxia were administered Cu-ATSM. Cu-ATSM is 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. In the control groups, death due to tumor burden occurred within 20 days weeks while animals with a dose greater than 6 mCi of the radioisotope tumor growth was inhibited and survival increased to 135 days in 50% of animals. The results also suggested that multiple doses and a single dose of 10 mCi were equally effective while the multiple dose regimen is safer for non-target tissue.[9]

Radiotherapy of cancer cells using ⁶⁴Cu can be applied in medical research and clinical practice. The advantages of radiotherapy with beta emitters of this energy are that there is enough to do substantial damage to the target cells but the mean range in tissue is less than a millimeter so non target tissues are unlikely to be harmed.[9] In addition, ⁶⁴Cu is a positron emitter making it a viable PET imaging radionuclide which can give real time images of the physiological processes in the system. These abilities in conjunction enable accurate monitoring of drug distribution and biokinetics simultaneously. Radiotherapeutic efficacy of copper-64 depends highly upon the radioligand delivery to the target cells, so the development of bifunctional chelates is central to development of ⁶⁴Cu's potential as a radiopharmaceutical.

References

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.
Welch, Michael; Redvanly, Carol S. (2003). Handbook of Radiopharmaceuticals : radiochemistry and applications. New York: Wiley. doi:10.1002/0470846380. ISBN 9780471495604.
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.
Welch, Michael J.; Redvanly, Carol S. (2003). Handbook of Radiopharmaceuticals: Radiochemistry and Applications. John Wiley & Sons. p. 407. ISBN 978-0-471-49560-4.
Bass, Laura A.; Wang, Mu; Welch, Michael J.; Anderson, Carolyn J. (July 2000). "In Vivo Transchelation of Copper-64 from TETA-Octreotide to Superoxide Dismutase in Rat Liver". Bioconjugate Chemistry. 11 (4): 527–532. doi:10.1021/bc990167l. PMID 10898574.
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.
Sprague, Jennifer E.; Peng, Yijie; Fiamengo, Ashley L.; Woodin, Katrina S.; Southwick, Evan A.; Weisman, Gary R.; Wong, Edward H.; Golen, James A.; Rheingold, Arnold L.; Anderson, Carolyn J. (May 2007). "Synthesis, Characterization and In Vivo Studies of Cu(II)-64-Labeled Cross-Bridged Tetraazamacrocycle-amide Complexes as Models of Peptide Conjugate Imaging Agents". Journal of Medicinal Chemistry. 50 (10): 2527–2535. doi:10.1021/jm070204r. PMID 17458949.
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.
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.