Copper-64 is a radioactive nuclide

Nuclide

A nuclide is an atomic species characterized by the specific constitution of its nucleus, i.e., by its number of protons Z, its number of neutrons N, and its nuclear energy state....

 of copper

Copper

Copper is a chemical element with the symbol Cu and atomic number 29. It is a ductile metal with very high thermal and electrical conductivity. Pure copper is soft and malleable; an exposed surface has a reddish-orange tarnish...

 which has unique decay

Radioactive decay

Radioactive decay is the process by which an atomic nucleus of an unstable atom loses energy by emitting ionizing particles . The emission is spontaneous, in that the atom decays without any physical interaction with another particle from outside the atom...

 properties making it useful in nuclear medicine

Nuclear medicine

In nuclear medicine procedures, elemental radionuclides are combined with other elements to form chemical compounds, or else combined with existing pharmaceutical compounds, to form radiopharmaceuticals. These radiopharmaceuticals, once administered to the patient, can localize to specific organs...

 for both imaging

Medical imaging

Medical imaging is the technique and process used to create images of the human body for clinical purposes or medical science...

 and therapy

Radiation therapy

Radiation therapy , radiation oncology, or radiotherapy , sometimes abbreviated to XRT or DXT, is the medical use of ionizing radiation, generally as part of cancer treatment to control malignant cells.Radiation therapy is commonly applied to the cancerous tumor because of its ability to control...

.

Properties

⁶⁴Cu has a half-life

Half-life

Half-life, abbreviated t½, is the period of time it takes for the amount of a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but it may apply to any quantity which follows a set-rate decay.The original term, dating to...

 of 12.701 ± 0.002 hours and decays by 17.86 (± 0.14)% by positron emission

Positron emission

Positron emission or beta plus decay is a type of beta decay in which a proton is converted, via the weak force, to a neutron, releasing a positron and a neutrino....

 to ⁶⁴Ni, 39.0 (± 0.3)% by beta decay

Beta decay

In nuclear physics, beta decay is a type of radioactive decay in which a beta particle is emitted from an atom. There are two types of beta decay: beta minus and beta plus. In the case of beta decay that produces an electron emission, it is referred to as beta minus , while in the case of a...

 to ⁶⁴Zn, 43.075 (± 0.500)% by electron capture

Electron capture

Electron capture is a process in which a proton-rich nuclide absorbs an inner atomic electron and simultaneously emits a neutrino...

 ⁶⁴Ni, and 0.475 (± 0.010)% gamma radiation/internal conversion

Internal conversion

Internal conversion is a radioactive decay process where an excited nucleus interacts with an electron in one of the lower atomic orbitals, causing the electron to be emitted from the atom. Thus, in an internal conversion process, a high-energy electron is emitted from the radioactive atom, but...

. These emissions are 0.5787 (± 0.0009) and 0.6531 (± 0.0002) MeV for beta minus and positron respectively and 1.35477 (± 0.00016) MeV for gamma.

The main oxidation state

Oxidation state

In chemistry, the oxidation state is an indicator of the degree of oxidation of an atom in a chemical compound. The formal oxidation state is the hypothetical charge that an atom would have if all bonds to atoms of different elements were 100% ionic. Oxidation states are typically represented by...

s of copper

Copper

Copper is a chemical element with the symbol Cu and atomic number 29. It is a ductile metal with very high thermal and electrical conductivity. Pure copper is soft and malleable; an exposed surface has a reddish-orange tarnish...

 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.

Copper is essential in the human body as both a catalyst and as part of enzymes. Copper is mainly involved in redox

Redox

Redox reactions describe all chemical reactions in which atoms have their oxidation state changed....

 reactions throughout the body, but also plays a role in iron transportation in blood plasma

Blood plasma

Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...

.

Production

Copper-64 can be technically reproduced by several different reactions with the most common methods using either a reactor

Research reactor

Research reactors are nuclear reactors that serve primarily as a neutron source. They are also called non-power reactors, in contrast to power reactors that are used for electricity production, heat generation, or maritime propulsion.-Purpose:...

 or an accelerator

Particle accelerator

A particle accelerator is a device that uses electromagnetic fields to propel charged particles to high speeds and to contain them in well-defined beams. An ordinary CRT television set is a simple form of accelerator. There are two basic types: electrostatic and oscillating field accelerators.In...

. Thermal neutrons can produce ⁶⁴Cu in low specific activity (the number of decays per second per amount of substance) and low yield

Yield (chemistry)

In chemistry, yield, also referred to as chemical yield and reaction yield, is the amount of product obtained in a chemical reaction. The absolute yield can be given as the weight in grams or in moles...

 through the ⁶³Cu(n,γ)⁶⁴Cu reaction. At the University of Missouri Research Reactor Center

University of Missouri Research Reactor Center

The University of Missouri Research Reactor Center is home to a tank-type nuclear research reactor that serves the University of Missouri's . The MURR is currently the highest power university research reactor in the U.S. at 10 megawatt thermal output...

 (MURR) ⁶⁴Cu was produced using high-energy neutrons via the ⁶⁴Zn(n,p)⁶⁴Cu reaction

Nuclear reaction

In nuclear physics and nuclear chemistry, a nuclear reaction is semantically considered to be the process in which two nuclei, or else a nucleus of an atom and a subatomic particle from outside the atom, collide to produce products different from the initial particles...

 in high specific activity but low yield. Using a biomedical cyclotron

Cyclotron

In technology, a cyclotron is a type of particle accelerator. In physics, the cyclotron frequency or gyrofrequency is the frequency of a charged particle moving perpendicularly to the direction of a uniform magnetic field, i.e. a magnetic field of constant magnitude and direction...

 the ⁶⁴Ni(p,n)⁶⁴Cu nuclear reaction can produce large quantities of the nuclide with high specific activity.

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-ETS2

Ethylglyoxal bis(thiosemicarbazone) has potential utility as a PET

Positron emission tomography

Positron emission tomography is nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide , which is introduced into the body on a...

 radiopharmaceutical with the various isotopes of copper. ⁶²Cu can be produced by a generator from the decay of ⁶²Zn and has a half-life of under 10 minutes. It has also been used for myocardial, cerebral and tumor profusion evaluations. ⁶⁴Cu has a much longer half-life and can be used with Cu-ETS as well since there is a linear relationship between the renal uptake and blood flow. Renal perfusion

Perfusion

In physiology, perfusion is the process of nutritive delivery of arterial blood to a capillary bed in the biological tissue. The word is derived from the French verb "perfuser" meaning to "pour over or through."...

 can also be evaluated with CT

Computed tomography

X-ray computed tomography or Computer tomography , is a medical imaging method employing tomography created by computer processing...

 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

Ionizing radiation

Ionizing radiation is radiation composed of particles that individually have sufficient energy to remove an electron from an atom or molecule. This ionization produces free radicals, which are atoms or molecules containing unpaired electrons...

. 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.

Dissociation of Copper from bifunctional chelates

The in vivo

In vivo

In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...

 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

Somatostatin

Somatostatin is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G-protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones.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

Superoxide dismutase

Superoxide dismutases are a class of enzymes that catalyze the dismutation of superoxide into oxygen and hydrogen peroxide. As such, they are an important antioxidant defense in nearly all cells exposed to oxygen...

 (SOD) in rat liver was investigated by utilizing a gel electrophoresis

Electrophoresis

Electrophoresis, also called cataphoresis, is the motion of dispersed particles relative to a fluid under the influence of a spatially uniform electric field. This electrokinetic phenomenon was observed for the first time in 1807 by Reuss , who noticed that the application of a constant electric...

 assay

Assay

An assay is a procedure in molecular biology for testing or measuring the activity of a drug or biochemical in an organism or organic sample. A quantitative assay may also measure the amount of a substance in a sample. Bioassays and immunoassays are among the many varieties of specialized...

 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.

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.

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.

Cancer Detection with Bombesin Analogs

The Bombesin

Bombesin

Bombesin is a 14-amino acid peptide originally isolated from the skin of a frog. It has two known homologs in mammals called neuromedin B and gastrin-releasing peptide. It stimulates gastrin release from G cells. It activates three different G-protein-coupled receptors known as BBR1, -2, and -3. It...

 peptide has been shown to be overexpressed in BB2 receptors in prostate cancer

Prostate cancer

Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...

. 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 xenographs 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.

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

Hypoxia (medical)

Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...

 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 4 weeks while animals with a dose greater than 6 mCi of the radioisotope tumor growth was inhibited and survival increased. 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.

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. In addition, ⁶⁴Cu is a positron emitter making it a viable PET imaging radionuclide

Radionuclide

A radionuclide is an atom with an unstable nucleus, which is a nucleus characterized by excess energy available to be imparted either to a newly created radiation particle within the nucleus or to an atomic electron. The radionuclide, in this process, undergoes radioactive decay, and emits gamma...

 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. With sufficient development, ⁶⁴Cu is likely to become a central element in nuclear medicine in the years to come.