Oxygen-15 labelled water

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Oxygen-15 labelled water
Skaermbillede 2019-02-04 kl. 08.27.53.png
Names
Other names
15O-water, [O-15]-H2O, H215O
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
PubChem CID
UNII
  • [15OH2]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Oxygen-15 labelled water (also known as 15O-water, [O-15]-H2O, or H215O) is a radioactive variation of regular water, in which the oxygen atom has been replaced by oxygen-15 (15O), a positron-emitting isotope. 15O-water is used as a radioactive tracer for measuring and quantifying blood flow using positron emission tomography (PET) in the heart, brain and tumors.

Contents

Due to its free diffusibility, 15O-water is considered the non-invasive gold standard 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 (SPECT), cardiac magnetic resonance imaging (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 that can accelerate deuterons up to a kinetic energy of approximately 7  MeV. [1]

Alternatives methods are:

15N(p,n)15O, in which low-energy protons (≈ 5 MeV) are used to transmute nitrogen into oxygen-15, [2] or 16O(p,pn)15O in which high-energy protons (> 16.6 MeV) are used. [3] [4] They all produce the radioactive isotope oxygen-15 by knocking neutrons out of the target molecule where the oxygen-15 ion combines with an oxygen atom to form the stable oxygen gas [15O]O2:

Conversion of 15O gas to 15O-water

The conversion of the oxygen gas [15O]O2 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 (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. [5]

The external out-of-target method converts oxygen-15 and H2 using heat and is used for all three nuclear reactions. Palladium is typically used as a catalyst to lower the activation energy. 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. [5]

Use in PET

Oxygen-15 decays with a half-life of about 2.04 minutes to nitrogen-15, emitting a positron. [6] The positron quickly annihilates with an electron, producing two gamma rays of about 511 keV which are detectable using a PET scanner.[ citation needed ]

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 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. [7]

Graphical representation of the relationship between absolute myocardial blood flow and tracer uptake for PET radiotracers. Also included Tc-Sestamibi, which is a commonly used SPECT tracer. Absolute myocardial blood flow.png
Graphical representation of the relationship between absolute myocardial blood flow and tracer uptake for PET radiotracers. Also included Tc-Sestamibi, which is a commonly used SPECT tracer.

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). [5]

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. [8] 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.

Clinical interpretation of 15O-water PET

With 15O-water PET, the optimal cutoffs for detecting hemodynamically significant CAD measured by FFR have been determined to be < 2.3 mL/min/g for vasodilator stress MBF and < 2.5 for coronary flow reserve (CFR). [9] 15O-water PET has an accuracy of 85% for diagnosing hemodynamically significant epicardial stenoses in patients with no history of CAD, which is higher than with both SPECT and CCTA. [10] However, the accuracy is reduced to 75% in patients with previous myocardial infarctions and/or previous PCI. [11]

Patients are generally considered to have a perfusion defect if stress MBF is < 2.3 mL/min/g in at least 2 adjacent segments. [12] Patients with perfusion defects of at least 10% of the left ventricle should be referred for coronary angiography and if FFR is ≤ 0.8 they can be treated with PCI.

Besides hemodynamically significant epicardial stenoses, patients can also have coronary microvascular dysfunction (CMD). [13] If stress MBF is reduced in the entire left ventricle, then both CMD and balanced three-vessel disease are possible diagnoses. CMD is treated pharmacologically and balanced three-vessel disease is treated surgically with CABG. It can be difficult to differentiate between CMD and balanced three-vessel disease. [12] However, CMD is much more common than balanced three-vessel disease. Also, the calcium score from the CT scan can help in the differentiation. If the calcium score is high, then balanced three-vessel disease is more likely; and vice versa if the calcium score is low then CMD is more likely.

Pharmacopeia

The clinical use of 15O-water in routine is not widespread. Within the European Union, 15O-water is recognized as a radiopharmaceutical and regulated as a drug.[ citation needed ] A pharmacopeia 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.

Related Research Articles

<span class="mw-page-title-main">Positron emission tomography</span> Medical imaging technique

Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities including blood flow, regional chemical composition, and absorption. Different tracers are used for various imaging purposes, depending on the target process within the body.

<span class="mw-page-title-main">Single-photon emission computed tomography</span> Nuclear medicine tomographic imaging technique

Single-photon emission computed tomography is a nuclear medicine tomographic imaging technique using gamma rays. It is very similar to conventional nuclear medicine planar imaging using a gamma camera, but is able to provide true 3D information. This information is typically presented as cross-sectional slices through the patient, but can be freely reformatted or manipulated as required.

<span class="mw-page-title-main">Nuclear medicine</span> Medical specialty

Nuclear medicine or nucleology is a medical specialty involving the application of radioactive substances in the diagnosis and treatment of disease. Nuclear imaging, in a sense, is "radiology done inside out" because it records radiation emitted from within the body rather than radiation that is transmitted through the body from external sources like X-ray generators. In addition, nuclear medicine scans differ from radiology, as the emphasis is not on imaging anatomy, but on the function. For such reason, it is called a physiological imaging modality. Single photon emission computed tomography (SPECT) and positron emission tomography (PET) scans are the two most common imaging modalities in nuclear medicine.

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 tracing the path that the radioisotope follows from reactants to products. Radiolabeling or radiotracing is thus the radioactive form of isotopic labeling. In biological contexts, use of radioisotope tracers are sometimes called radioisotope feeding experiments.

<span class="mw-page-title-main">Scintigraphy</span> Diagnostic imaging test in nuclear medicine

Scintigraphy, also known as a gamma scan, is a diagnostic test in nuclear medicine, where radioisotopes attached to drugs that travel to a specific organ or tissue (radiopharmaceuticals) are taken internally and the emitted gamma radiation is captured by gamma cameras, which are external detectors that form two-dimensional images in a process similar to the capture of x-ray images. In contrast, SPECT and positron emission tomography (PET) form 3-dimensional images and are therefore classified as separate techniques from scintigraphy, although they also use gamma cameras to detect internal radiation. Scintigraphy is unlike a diagnostic X-ray where external radiation is passed through the body to form an image.

<span class="mw-page-title-main">Perfusion</span> Passage of fluid through the circulatory or lymphatic system to an organ or tissue

Perfusion is the passage of fluid through the circulatory system or lymphatic system to an organ or a tissue, usually referring to the delivery of blood to a capillary bed in tissue. Perfusion may also refer to fixation via perfusion, used in histological studies. Perfusion is measured as the rate at which blood is delivered to tissue, or volume of blood per unit time per unit tissue mass. The SI unit is m3/(s·kg), although for human organs perfusion is typically reported in ml/min/g. The word is derived from the French verb "perfuser" meaning to "pour over or through". All animal tissues require an adequate blood supply for health and life. Poor perfusion (malperfusion), that is, ischemia, causes health problems, as seen in cardiovascular disease, including coronary artery disease, cerebrovascular disease, peripheral artery disease, and many other conditions.

There are three known stable isotopes of oxygen (8O): 16
O
, 17
O
, and 18
O
.

<span class="mw-page-title-main">Bone scintigraphy</span>

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<span class="mw-page-title-main">Neuroimaging</span> Set of techniques to measure and visualize aspects of the nervous system

Neuroimaging is the use of quantitative (computational) techniques to study the structure and function of the central nervous system, developed as an objective way of scientifically studying the healthy human brain in a non-invasive manner. Increasingly it is also being used for quantitative research studies of brain disease and psychiatric illness. Neuroimaging is highly multidisciplinary involving neuroscience, computer science, psychology and statistics, and is not a medical specialty. Neuroimaging is sometimes confused with neuroradiology.

<span class="mw-page-title-main">Fluorine-18</span> Isotope of fluorine emitting a positron

Fluorine-18 (18F) is a fluorine radioisotope which is an important source of positrons. It has a mass of 18.0009380(6) u and its half-life is 109.771(20) minutes. It decays by positron emission 96% of the time and electron capture 4% of the time. Both modes of decay yield stable oxygen-18.

Myocardial stunning or transient post-ischemic myocardial dysfunction is a state of mechanical cardiac dysfunction that can occur in a portion of myocardium without necrosis after a brief interruption in perfusion, despite the timely restoration of normal coronary blood flow. In this situation, even after ischemia has been relieved and myocardial blood flow (MBF) returns to normal, myocardial function is still depressed for a variable period of time, usually days to weeks. This reversible reduction of function of heart contraction after reperfusion is not accounted for by tissue damage or reduced blood flow, but rather, its thought to represent a perfusion-contraction "mismatch". Myocardial stunning was first described in laboratory canine experiments in the 1970s where LV wall abnormalities were observed following coronary artery occlusion and subsequent reperfusion.

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<span class="mw-page-title-main">Myocardial perfusion imaging</span> Nuclear medicine imaging method

Myocardial perfusion imaging or scanning is a nuclear medicine procedure that illustrates the function of the heart muscle (myocardium).

Perfusion is the passage of fluid through the lymphatic system or blood vessels to an organ or a tissue. The practice of perfusion scanning is the process by which this perfusion can be observed, recorded and quantified. The term perfusion scanning encompasses a wide range of medical imaging modalities.

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<span class="mw-page-title-main">Cardiac imaging</span>

Cardiac imaging refers to minimally invasive imaging of the heart using ultrasound, magnetic resonance imaging (MRI), computed tomography (CT), or nuclear medicine (NM) imaging with PET or SPECT. These cardiac techniques are otherwise referred to as echocardiography, Cardiac MRI, Cardiac CT, Cardiac PET and Cardiac SPECT including myocardial perfusion imaging.

<span class="mw-page-title-main">Brain positron emission tomography</span> Form of positron emission tomography

Brain positron emission tomography is a form of positron emission tomography (PET) that is used to measure brain metabolism and the distribution of exogenous radiolabeled chemical agents throughout the brain. PET measures emissions from radioactively labeled metabolically active chemicals that have been injected into the bloodstream. The emission data from brain PET are computer-processed to produce multi-dimensional images of the distribution of the chemicals throughout the brain.

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References

  1. ↑ Clark, J.C (1987). "Current methodology for oxygen-15 production for clinical use". Int J Rad Appl Instrum A. 38 (8): 597–600. doi:10.1016/0883-2889(87)90122-5. PMID   2822617.
  2. ↑ Powell and O'Neil, James (2006). "Production of [O-15]water at low-energy proton cyclotrons". Applied Radiation and Isotopes. 64 (7): 755–759. doi:10.1016/j.apradiso.2006.02.096. PMID   16617023. S2CID   25033642.
  3. ↑ Beaver, J (1976). "A new method for the production of high concentration oxygen-15 labeled carbon dioxide with protons". Appl Radiat Isot. 27 (3): 195–197. doi:10.1016/0020-708X(76)90138-1.
  4. ↑ Krohn, K (1986). "The use of 50 MeV protons to produce C-11 and O-15". J Labelled Compd Radiopharm. 23: 1190–1192.
  5. 1 2 3 Dierckx, Rudi A.J.O. (2014). PET and SPECT of Neurobiological Systems. Springer.
  6. ↑ NNDC contributors (2008). Alejandro A. Sonzogni (Database Manager) (ed.). "Chart of Nuclides". Upton (NY): National Nuclear Data Center, Brookhaven National Laboratory . Retrieved 2019-02-08.{{cite web}}: |author= has generic name (help)
  7. ↑ Goode, A. W. (2015). Das, Birenda Kishore (ed.). Positron Emission Tomography: A Guide for Clinicians. p. 399. doi:10.1007/978-81-322-2098-5. ISBN   978-81-322-2097-8. PMC   1290883 .{{cite book}}: |journal= ignored (help)
  8. ↑ Heertum, Ronald L. Van; Tikofsky, Ronald S.; Ichise, Masanori (2013). Functional Cerebral SPECT and PET Imaging. Lippincott Williams & Wilkins. p. 16. ISBN   9781451153392.
  9. ↑ Danad, Ibrahim; Uusitalo, Valtteri; Kero, Tanja; Saraste, Antti; Raijmakers, Pieter G.; Lammertsma, Adriaan A.; Heymans, Martijn W.; Kajander, Sami A.; Pietilä, Mikko; James, Stefan; Sörensen, Jens; Knaapen, Paul; Knuuti, Juhani (2014-10-07). "Quantitative assessment of myocardial perfusion in the detection of significant coronary artery disease: cutoff values and diagnostic accuracy of quantitative [(15)O]H2O PET imaging". Journal of the American College of Cardiology. 64 (14): 1464–1475. doi: 10.1016/j.jacc.2014.05.069 . ISSN   1558-3597. PMID   25277618. S2CID   25351315.
  10. ↑ Danad, Ibrahim; Raijmakers, Pieter G.; Driessen, Roel S.; Leipsic, Jonathon; Raju, Rekha; Naoum, Chris; Knuuti, Juhani; Mäki, Maija; Underwood, Richard S.; Min, James K.; Elmore, Kimberly; Stuijfzand, Wynand J.; van Royen, Niels; Tulevski, Igor I.; Somsen, Aernout G. (2017-10-01). "Comparison of Coronary CT Angiography, SPECT, PET, and Hybrid Imaging for Diagnosis of Ischemic Heart Disease Determined by Fractional Flow Reserve". JAMA Cardiology. 2 (10): 1100–1107. doi:10.1001/jamacardio.2017.2471. ISSN   2380-6591. PMC   5710451 . PMID   28813561.
  11. ↑ Driessen, Roel S.; van Diemen, Pepijn A.; Raijmakers, Pieter G.; Knuuti, Juhani; Maaniitty, Teemu; Underwood, S. Richard; Nagel, Eike; Robbers, Lourens F. H. J.; Demirkiran, Ahmet; von Bartheld, Martin B.; van de Ven, Peter M.; Hofstra, Leonard; Somsen, G. Aernout; Tulevski, Igor I.; Boellaard, Ronald (2022-09-01). "Functional stress imaging to predict abnormal coronary fractional flow reserve: the PACIFIC 2 study". European Heart Journal. 43 (33): 3118–3128. doi:10.1093/eurheartj/ehac286. ISSN   1522-9645. PMC   9433308 . PMID   35708168.
  12. 1 2 Sciagrà, R (2021). "EANM procedural guidelines for PET/CT quantitative myocardial perfusion imaging". European Journal of Nuclear Medicine and Molecular Imaging. 48 (4): 1040–1069. doi:10.1007/s00259-020-05046-9. PMC   7603916 . PMID   33135093.
  13. ↑ Maaniitty, T (2020). "15O-Water PET MPI: Current Status and Future Perspectives". Seminars in Nuclear Medicine. 50 (3): 238–247. doi:10.1053/j.semnuclmed.2020.02.011. PMID   32284110. S2CID   215759629.
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