# Copper-64

Copper-64 ($^{64}$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

$^{64}$Cu has a half-life of 12.7 hours and decays 17.9% by positron emission to $^{64}$Ni, 39.0% by beta decay to $^{64}$Zn, 43.1% by electron capture to $^{64}$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 $^{64}$Cu in low specific activity (the number of decays per second per amount of substance) and low yield through the $^{63}$Cu(n,γ)$^{64}$Cu reaction. At the University of Missouri Research Reactor Center (MURR) $^{64}$Cu was produced using high-energy neutrons via the $^{64}$Zn(n,p)$^{64}$Cu nuclear reaction in high specific activity but low yield. Using a biomedical cyclotron the $^{64}$Ni(p,n)$^{64}$Cu nuclear reaction can produce large quantities of the nuclide with high specific activity.

## Applications

As a positron emitter, $^{64}$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 $^{64}$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 $^{64}$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 $^{64}$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. $^{64}$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 $^{64}$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. $^{64}$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

$^{64}$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. $^{64}$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.