Oxygen-15 labelled water (also known as ¹⁵O-water, -15H₂O, or H₂¹⁵O) is a radioactive variation of regular water, in which the

oxygen Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as wel ...

atom has been replaced by

oxygen-15 There are three known stable isotopes of oxygen (8O): , , and . Radioactive isotopes ranging from to have also been characterized, all short-lived. The longest-lived radioisotope is with a half-life of , while the shortest-lived isotope is ...

(¹⁵O), a

positron The positron or antielectron is the antiparticle or the antimatter counterpart of the electron. It has an electric charge of +1 '' e'', a spin of 1/2 (the same as the electron), and the same mass as an electron. When a positron collides ...

-emitting

isotope Isotopes are two or more types of atoms that have the same atomic number (number of protons in their nuclei) and position in the periodic table (and hence belong to the same chemical element), and that differ in nucleon numbers (mass numbers) ...

. ¹⁵O-water is used as a

radioactive tracer A radioactive tracer, radiotracer, or radioactive label is a chemical compound in which one or more atoms have been replaced by a radionuclide so by virtue of its radioactive decay it can be used to explore the mechanism of chemical reactions by ...

for measuring and quantifying

blood flow Hemodynamics or haemodynamics are the dynamics of blood flow. The circulatory system is controlled by homeostatic mechanisms of autoregulation, just as hydraulic circuits are controlled by control systems. The hemodynamic response continuously m ...

using

positron emission tomography Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in Metabolism, metabolic processes, and in other physiological activities including bl ...

(PET) in the heart, brain and

tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

s. Due to its free diffusibility, ¹⁵O-water is considered the non-invasive

gold standard A gold standard is a monetary system in which the standard economic unit of account is based on a fixed quantity of gold. The gold standard was the basis for the international monetary system from the 1870s to the early 1920s, and from the la ...

for quantitative myocardial blood flow (MBF) studies and has been used as reference standard for validations of other MBF quantification techniques, such as

single-photon emission computed tomography Single-photon emission computed tomography (SPECT, or less commonly, SPET) is a nuclear medicine tomographic imaging technique using gamma rays. It is very similar to conventional nuclear medicine planar imaging using a gamma camera (that is, ...

(SPECT),

cardiac magnetic resonance imaging Cardiac magnetic resonance imaging (cardiac MRI), also known as cardiovascular MRI, is a magnetic resonance imaging (MRI) technology used for non-invasive assessment of the function and structure of the cardiovascular system. Conditions in which it ...

(CMR) and dynamic computed tomography (CT).

Production of oxygen-15-water

Production of oxygen-15 gas

Oxygen-15 can be produced by different nuclear reactions, including ¹⁴N(d,n)¹⁵O, ¹⁶O(p,pn)¹⁵O and ¹⁵N(p,n)¹⁵O. The ¹⁴N(d,n)¹⁵O production route is the most frequently applied method, because it is currently the most economic method. The production requires a

cyclotron A cyclotron is a type of particle accelerator invented by Ernest O. Lawrence in 1929–1930 at the University of California, Berkeley, and patented in 1932. Lawrence, Ernest O. ''Method and apparatus for the acceleration of ions'', filed: Janu ...

that can accelerate

deuteron Deuterium (or hydrogen-2, symbol or deuterium, also known as heavy hydrogen) is one of two stable isotopes of hydrogen (the other being protium, or hydrogen-1). The nucleus of a deuterium atom, called a deuteron, contains one proton and one n ...

s up to a kinetic energy of approximately 7

MeV In physics, an electronvolt (symbol eV, also written electron-volt and electron volt) is the measure of an amount of kinetic energy gained by a single electron accelerating from rest through an Voltage, electric potential difference of one volt i ...

. Alternatives methods are: ¹⁵N(p,n)¹⁵O, in which low-energy

proton A proton is a stable subatomic particle, symbol , H+, or 1H+ with a positive electric charge of +1 ''e'' elementary charge. Its mass is slightly less than that of a neutron and 1,836 times the mass of an electron (the proton–electron mass ...

s (≈ 5 MeV) are used to transmute nitrogen into oxygen-15, or ¹⁶O(p,pn)¹⁵O in which high-energy protons (> 16.6 MeV) are used. They all produce the radioactive isotope oxygen-15 by knocking

neutron The neutron is a subatomic particle, symbol or , which has a neutral (not positive or negative) charge, and a mass slightly greater than that of a proton. Protons and neutrons constitute the nuclei of atoms. Since protons and neutrons beh ...

s out of the target molecule where the oxygen-15 ion combines with an oxygen atom to form the stable oxygen gas sup>15O₂: ^_N + ^_D -> ^_O^2- +n 2^_O^2- + N_2 -> 2 NO 2 NO -> 15O_2 + N_2

Conversion of ¹⁵O gas to ¹⁵O-water

The conversion of the oxygen gas sup>15O₂ to ¹⁵O-water can happen in two ways: the in-target production and the out-of-target external conversion. The in-target production method uses a small amount of

hydrogen Hydrogen is the chemical element with the symbol H and atomic number 1. Hydrogen is the lightest element. At standard conditions hydrogen is a gas of diatomic molecules having the formula . It is colorless, odorless, tasteless, non-toxic, an ...

(about 5%) that is added to the gas, whereby ¹⁵O-water is formed and trapped in a cooled stainless steel loop. By heating the loop the ¹⁵O-water will get released and will be trapped again in a saline solution. It could also be done by directly irradiating H₂¹⁶O. However, this method requires high-energy protons and is therefore used less. The external out-of-target method converts oxygen-15 and H₂ using heat and is used for all three nuclear reactions.

Palladium Palladium is a chemical element with the symbol Pd and atomic number 46. It is a rare and lustrous silvery-white metal discovered in 1803 by the English chemist William Hyde Wollaston. He named it after the asteroid Pallas, which was itself na ...

is typically used as a

catalyst Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...

to lower the

activation energy In chemistry and physics, activation energy is the minimum amount of energy that must be provided for compounds to result in a chemical reaction. The activation energy (''E''a) of a reaction is measured in joules per mole (J/mol), kilojoules pe ...

. The mixture of the target gas, the catalyst and H₂ is then heated up, which results in a release of ¹⁵O-water vapor, which then bubbles into a saline solution and is drawn into a syringe where it can be applied to the subject.

Use in PET

Oxygen-15 decays with a

half-life Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable ato ...

of about 2.04 minutes to nitrogen-15, emitting a positron. The positron quickly annihilates with an electron, producing two gamma rays of about 511 keV which are detectable using a PET scanner. Of several available PET tracers for quantification of myocardial blood flow (MBF), ⁸²Rb, ¹³NH₃, and H₂¹⁵O are most commonly used. (see the table below). ¹⁵O-water features different properties compared to ⁸²Rb and ¹³NH₃. ¹⁵O-water is metabolically inert and diffuses freely across the

myocyte A muscle cell is also known as a myocyte when referring to either a cardiac muscle cell (cardiomyocyte), or a smooth muscle cell as these are both small cells. A skeletal muscle cell is long and threadlike with many nuclei and is called a muscl ...

membrane in contrast to ⁸²Rb and ¹³NH₃, which enter the cell via active diffusion (¹³NH₃ diffuses both actively and passively). ¹³NH₃ is converted to glutamine, glutamic acid and carbamoyl phosphate in the tissue and becomes metabolically bound. ¹⁵O-water has a 100% extraction rate, which makes ¹⁵O-water superior to ⁸²Rb and ¹³NH₃ as no flow-dependent extraction corrections are required. Its 2-minute half-life makes it possible to acquire multiple image scans in rapid sequence. However, due to the complete extraction and free diffusibility, ¹⁵O-water is not retained in the tissue of interest and post-processing is required to convert ¹⁵O-water images to quantitative blood flow images. Absolute myocardial blood flow

Limitations

A technical limitation of ¹⁵O-water is the challenge in separating the blood activity from the myocardial tissue activity. This challenge arises from the tracer's free diffusion and from the fact that the tracer is metabolically inert. However, these issues have been overcome by recent advances in both hardware and software. ¹⁵O-water has now been used in several clinical trials (pivotal studies). Another limitation for the tracer's widespread uptake has been its historical cost. A cyclotron is necessary for the production of ¹⁵O-water, requiring large capital investment in hardware and skilled staff to operate the production. However, ongoing development aims to reduce the capital expenditure and limit the amount of skilled personnel involved in the production, making ¹⁵O-water available for clinical practice.

Pharmacopeia

The clinical use of ¹⁵O-water in routine is not widespread. Within the

European Union The European Union (EU) is a supranational political and economic union of member states that are located primarily in Europe. The union has a total area of and an estimated total population of about 447million. The EU has often been des ...

, ¹⁵O-water is recognized as a

radiopharmaceutical Radiopharmaceuticals, or medicinal radiocompounds, are a group of pharmaceutical drugs containing radioactive isotopes. Radiopharmaceuticals can be used as diagnostic and therapeutic agents. Radiopharmaceuticals emit radiation themselves, which is ...

and regulated as a drug. A

pharmacopeia A pharmacopoeia, pharmacopeia, or pharmacopoea (from the obsolete typography ''pharmacopœia'', meaning "drug-making"), in its modern technical sense, is a book containing directions for the identification of compound medicines, and published by ...

monograph exists, allowing hospital facilities to produce and use ¹⁵O-water within the confines of their national legislation. In the US, ¹⁵O-water is recognized as a radiopharmaceutical and regulated as a drug, but no pharmacopeia monograph exists currently.

References

{{Reflist Cardiac imaging Radiopharmaceuticals PET radiotracers Water