Medical Isotopes : General Concepts

ISOTOPES

An isotope is one of two or more species of atoms of a chemical element with the same atomic number (same number or protons in the nucleus) and position in the periodic table and nearly identical chemical behavior but with different atomic masses and physical properties. Every chemical element has one or more isotopes.

An atom is first identified and labeled according to the number of protons in its nucleus. This atomic number is ordinarily given the symbol Z. The great importance of the atomic number derives from the observation that all atoms with the same atomic number have nearly, if not precisely, identical chemical properties. A large collection of atoms with the same atomic number constitutes a sample of an element. A bar of pure uranium, for instance, would consist entirely of atoms with atomic number 92. The periodic table of the elements assigns one place to every atomic number, and each of these places is labeled with

the common name of the element, as, for example, calcium, radon, or uranium. Not all the atoms of an element need have the same number of neutrons in their nuclei. In fact, it is precisely the variation in the number of neutrons in the nuclei of atoms that gives rise to isotopes. Hydrogen is a case in point. It has the atomic number 1. Three nuclei with one proton are known that contain 0, 1, and 2 neutrons, respectively. The three share the place in the periodic table assigned to

atomic number 1 and hence are called isotopes (from the Greek isos, meaning "same," and topos, signifying "place") of hydrogen. Many important properties of an isotope depend on its mass. The total number of neutrons and protons (symbol A), or mass number, of the nucleus gives approximately the mass measured on the so-called atomic- mass-unit (amu) scale. The numerical difference between the actual measured mass of an isotope and A is called the mass defect.

The specification of Z, A, and the chemical symbol (a one- or two-letter abbreviation of the element's name, say Sy) in the form A/ZSy identifies an isotope adequately for most purposes. Thus in the standard notation, 1/1H refers to the simplest isotope of hydrogen and 235/92U to an isotope of uranium widely used for nuclear power generation and nuclear weapons fabrication. (Authors who do not wish to use symbols sometimes write out the element name and mass number‹hydrogen-1 and uranium-235 in the examples above.)

STABLE AND UNSTABLE ISOTOPES

Isotopes utilized in nuclear medicine fall into two broad categories: Stable and Unstable. Stable isotopes do not undergo radioactive decay. WHAT IS A STABLE ISOTOPE?

A "stable isotope" is any of two or more forms of an element whos nuclei contains the same number of protons and electrons, but a different number of neutrons. Stable isotopes remain unchanged indefinitely,

but "unstable" (radioactive) isotopes undergo spontaneous disintegration. An "isotopically labeled compound" has one or more of its atoms enriched in an isotope.

APPLICATIONS

Stable isotopes are tools used by researchers worldwide in the diagnosis of disease, to understand metabolic pathways in humans, and to answer fundamental questions in nature. They help researchers find answers by allowing them to look at a problem in a new way, from a different perspective. They help to better understand a process, trace a compound from a particular source, measure the concentration of

a chemical in a sample, or measure the rate of a related process. Stable isotopes already play an important role in research today and will become even more important to research in the future.

Examples of stable elements used in nuclear medicine isotopes such as carbon-13, nitrogen-15 and oxygen-18 as well as noble gas isotopes. Uses of stable isotopes include the custom synthesis of new and complex labeled compounds to use in agriculture, biology, chemistry, drug testing, geology, health, nutrition, physics as well as diagnostic techniques in medicine.

WHAT ARE RADIOISOTOPES ?

Many of the chemical elements have a number of isotopes. The isotopes of an element have the same

number of protons in their atoms (atomic number) but different masses due to different numbers of neutrons. In an atom in the neutral state, the number of external electrons also equals the atomic number. These electrons determine the chemistry of the atom. The atomic mass is the sum of the protons and neutrons. There are 82 stable elements and about 275 stable isotopes of these elements.

When a combination of neutrons and protons, which does not already exist in nature, is produced artificially, the atom will be unstable and is called a radioactive isotope or radioisotope. There are also a number of unstable natural isotopes arising from the decay of primordial uranium and thorium. Overall there are some 3800 radioisotopes. At present there are up to 200 radioisotopes used on a

regular basis, and most must be produced artificially. Radioisotopes can be manufactured in several ways. The most common is by neutron activation in a

nuclear reactor. This involves the capture of a neutron by the nucleus of an atom resulting in an excess of neutrons (neutron rich). Some radioisotopes are manufactured in a cyclotron in which protons are introduced to the nucleus resulting in a deficiency of neutrons (proton rich).

The nucleus of a radioisotope usually becomes stable by emitting an alpha and/or beta particle (or positron). These particles may be accompanied by the emission of energy in the form of electromagnetic radiation known as gamma rays. This process is known as radioactive decay. Radioactive products which are used in medicine are referred to as radiopharmaceuticals.

NUCLEAR MEDICINE

This is a branch of medicine that uses radiation to provide information about the functioning of a person's specific organs or to treat disease. In most cases, the information is used by physicians to make a quick,

accurate diagnosis of the patient's illness. The thyroid, bones, heart, liver and many other organs can be easily imaged, and disorders in their function revealed. In some cases radiation can be used to treat diseased organs, or tumors. In developed countries (26% of world population) the frequency of diagnostic nuclear medicine is 1.9% per year, and the frequency of therapy with radioisotopes is about one tenth of this.

Nuclear medicine was developed in the 1950s by physicians with an endocrine emphasis, initially using iodine-131 to diagnose and then treat thyroid disease. In recent years specialists have also come from radiology, as dual CT/PET procedures have become established.

DIAGNOSIS

Diagnostic techniques in nuclear medicine use radioactive tracers which emit gamma rays from within the

body. These tracers are generally short- lived isotopes linked to chemical compounds which permit specific physiological processes to be scrutinised. They can be given by injection, inhalation or orally. The

first type are where single photons are detected by a gamma camera which can view organs from many different angles. The camera builds up an image from the points from which radiation is emitted; this image is enhanced by a computer and viewed by a physician on a monitor for indications of abnormal conditions. A more recent development is Positron Emission Tomography (PET) which is a more precise and sophisticated technique using isotopes produced in a cyclotron. A positron-emitting radionuclide is

introduced, usually by injection, and accumulates in the target tissue. As it decays it emits a positron, which promptly combines with a nearby electron resulting in the simultaneous emission of two identifiable gamma rays in opposite directions. These are detected by a PET camera and give very precise indication of their origin. PET's most important clinical role is in oncology, with fluorine-18 as the tracer, since it has

proven to be the most accurate non-invasive method of detecting and evaluating most cancers. It is also well used in cardiac and brain imaging.

New procedures combine PET with CT scans to give co-registration of the two images, enabling 30% better diagnosis than with traditional gamma camera alone.

Positioning of the radiation source within the body makes the fundamental difference between nuclear medicine imaging and other imaging techniques such as x-rays. Gamma imaging by either method

described provides a view of the position and concentration of the radioisotope within the body. Organ malfunction can be indicated if the isotope is either partially taken up in the organ (cold spot) or taken up in excess (hot spot). If a series of images is taken over a period of time, an unusual pattern or rate of isotope movement could indicate malfunction in the organ.

A distinct advantage of nuclear imaging over x-ray techniques is that both bone and soft tissue can be imaged very successfully. This has led to its common use in developed countries where the probability of anyone having such a test is about one in two and rising. The mean effective dose is 4.6 mSv per diagnostic procedure.

RADIOTHERAPY

Rapidly dividing cells are particularly sensitive to damage by radiation. For this reason, some cancerous

growths can be controlled or eliminated by irradiating the area containing the growth. External irradiation

can be carried out using a gamma beam from a radioactive cobalt-60 source, though in developed countries the much more versatile linear accelerators are now being utilised as a high-energy x-ray source (gamma and x-rays are much the same). Internal radiotherapy is by administering or planting a small radiation source, usually a gamma or beta emitter, in the target area. Iodine-131 is commonly used to treat thyroid cancer, probably the most

successful kind of cancer treatment. It is also used to treat non-malignant thyroid disorders. Iridium-192 implants are used especially in the head and breast. They are produced in wire form and are introduced through a catheter to the target area. After administering the correct dose, the implant wire is removed to shielded storage. This brachytherapy (short-range) procedure gives less overall radiation to the body, is more localised to the target tumour and is cost effective. Treating leukaemia may involve a bone marrow transplant, in which case the defective bone marrow will

first be killed off with a massive (and otherwise lethal) dose of radiation before being replaced with healthy bone marrow from a donor. Many therapeutic procedures are palliative, usually to relieve pain. For instance, strontium-89 and (increasingly) samarium 153 are used for the relief of cancer-induced bone pain. Rhenium-186 is a newer product for this.

A new field is targeted alpha therapy (TAT), especially for the control of dispersed cancers. The short range of very energetic alpha emissions in tissue means that a large fraction of that radiative energy goes into the targeted cancer cells, once a carrier has taken the alpha-emitting radionuclide to exactly the right place. Laboratory studies are encouraging and clinical trials for leukaemia, cystic glioma and melanoma are under way.

An experimental development of this is neutron capture therapy using boron-10 which concentrates in malignant brain tumours. The patient is then irradiated with thermal neutrons which are strongly absorbed by the boron, producing high-energy alpha particles which kill the cancer. This requires the patient to be brought to a nuclear reactor, rather than the radioisotopes being taken to the patient. With any therapeutic procedure the aim is to confine the radiation to well- defined target volumes of the patient. The doses per therapeutic procedure are typically 20-60 Gy.

BIOCHEMICAL ANALYSIS

It is very easy to detect the presence or absence of some radioactive materials even when they exist in very low concentrations. Radioisotopes can therefore be used to label molecules of biological samples in vitro (out of the body). Pathologists have devised hundreds of tests to determine the constituents of

blood, serum, urine, hormones, antigens and many drugs by means of associated radioisotopes. These procedures are known as radioimmuno assays and, although the biochemistry is complex, kits manufactured for laboratory use are very easy to use and give accurate results.

DIAGNOSTIC RADIOPHARMACEUTICALS

Every organ in our bodies acts differently from a chemical point of view. Doctors and chemists have

identified a number of chemicals which are absorbed by specific organs. The thyroid, for example, takes up iodine, the brain consumes quantities of glucose, and so on. With this knowledge, radiopharmacists are able to attach various radioisotopes to biologically active substances. Once a radioactive form of one of these substances enters the body, it is incorporated into the normal biological processes and excreted

in the usual ways. Diagnostic radiopharmaceuticals can be used to examine blood flow to the brain, functioning of the liver, lungs, heart or kidneys, to assess bone growth, and to confirm other diagnostic procedures. Another important use is to predict the effects of surgery and assess changes since treatment. The amount of the radiopharmaceutical given to a patient is just sufficient to obtain the required information before its

decay. The radiation dose received is medically insignificant. The patient experiences no discomfort during the test and after a short time there is no trace that the test was ever done. The non-invasive nature of this technology, together with the ability to observe an organ functioning from outside the

body, makes this technique a powerful diagnostic tool. A radioisotope used for diagnosis must emit gamma rays of sufficient energy to escape from the body and it must have a half-life short enough for it to decay away soon after imaging is completed.

The radioisotope most widely used in medicine is technetium-99m, employed in some 80% of all nuclear medicine procedures. It is an isotope of the artificially-produced element technetium and it has almost ideal characteristics for a nuclear medicine scan. These are: It has a half-life of six hours which is long enough to examine metabolic processes yet short enough to minimise the radiation dose to the patient. Technetium-99m decays by a process called "isomeric"; which emits gamma rays and low energy electrons. Since there is no high energy beta emission the radiation dose to the patient is low.

The low energy gamma rays it emits easily escape the human body and are accurately detected by a

gamma camera. Once again the radiation dose to the patient is minimized. The chemistry of technetium is so versatile it can form tracers by being incorporated into a range of biologically-active substances to ensure that it concentrates in the tissue or organ of interest.

Its logistics also favour its use. Technetium generators, a lead pot enclosing a glass tube containing the radioisotope, are supplied to hospitals from the nuclear reactor where the isotopes are made. They contain molybdenum-99, with a half-life of 66 hours, which progressively decays to technetium-99. The Tc-99 is washed out of the lead pot by saline solution when it is required. After two weeks or less the generator is returned for recharging.

A similar generator system is used to produce rubidium-82 for PET imaging from strontium-82 – which has a half-life of 25 days. Myocardial Perfusion Imaging (MPI) uses thallium-201 chloride or technetium-

99m and is important for detection and prognosis of coronary artery disease. For PET imaging, the main radiopharmaceutical is Fluoro-deoxy glucose (FDG) incorporating F-18 – with a half-life of just under two hours, as a tracer. The FDG is readily incorporated into the cell without being broken down, and is a good indicator of cell metabolism.

In diagnostic medicine, there is a strong trend to using more cyclotron- produced isotopes such as F-18 as PET and CT/PET become more widely available. However, the procedure needs to be undertaken within two hours of a cyclotron.

THERAPEUTIC RADIOPHARMACEUTICALS

For some medical conditions, it is useful to destroy or weaken malfunctioning cells using radiation. The radioisotope that generates the radiation can be localised in the required organ in the same way it is used

for diagnosis – through a radioactive element following its usual biological path, or through the element being attached to a suitable biological compound. In most cases, it is beta radiation which causes the destruction of the damaged cells. This is radiotherapy. Short-range radiotherapy is known as brachytherapy. Although radiotherapy is less common than diagnostic use of radioactive material in medicine, it is

nevertheless widespread, important and growing. An ideal therapeutic radioisotope is a beta emitter with just enough gamma to enable imaging, eg lutetium-177.

Iodine-131 and phosphorus-32 are examples of two radioisotopes used for therapy. Iodine-131 is used to treat the thyroid for cancers and other abnormal conditions such as hyperthyroidism (over-active thyroid). In a disease called Polycythemia vera, an excess of red blood cells is produced in the bone marrow. Phosphorus-32 is used to control this excess.

A new and still experimental procedure uses boron-10 which concentrates in the tumor. The patient is then irradiated with neutrons which are strongly absorbed by the boron, to produce high-energy alpha particles which kill the cancer. For targeted alpha therapy (TAT), actinium-225 is readily available now, from which the daughter Bi-213

can be obtained (via 3 alpha decays) to label targeting molecules.

Considerable medical research is being conducted worldwide into the use of radionuclides attached to highly specific biological chemicals such as immunoglobulin molecules (monoclonal antibodies). The eventual tagging of these cells with a therapeutic dose of radiation may lead to the regression – or even cure – of some diseases.

THE DISCOVERY OF ISOTOPES

Evidence for the existence of isotopes emerged from two independent lines of research, the first being the study of radioactivity. By 1910 it had become clear that certain processes associated with radioactivity, discovered some years before by Henri Becquerel, could transform one element into another. In particular, ores of the radioactive elements uranium and thorium had been found to contain small quantities of several radioactive substances never before observed. These substances were thought to be elements and accordingly received special names. Uranium ores, for example, yielded "ionium," and thorium ores gave "mesothorium." Painstaking work completed soon afterward revealed, however, that

ionium, once mixed with ordinary thorium, could no longer be retrieved by chemical means alone. Similarly, mesothorium was shown to be chemically indistinguishable from radium. As chemists used the criterion of chemical indistinguishability as part of the definition of an element, they were forced to conclude that ionium and mesothorium were not new elements after all, but rather new forms of old ones. Generalizing from these and other data, Frederick Soddy in 1910 observed that "elements of different atomic weights may possess identical (chemical) properties" and so belong in the same place in the periodic table. With considerable prescience, he extended the scope of his conclusion to include not

only radioactive species but stable elements as well. A few years later, Soddy published a comparison of the atomic weights of the stable element lead as measured in ores rich in uranium and thorium, respectively. He expected a difference because uranium and thorium decay into different isotopes of lead. The lead from the uranium-rich ore had an average atomic weight of 206.08 compared to 207.69 for the lead from the thorium-rich ore, thus verifying Soddy's conclusion.

The unambiguous confirmation of isotopes in stable elements not associated directly with either uranium or thorium followed a few years later with the development of the mass spectrograph by Francis William Aston. His work grew out of the study of positive rays (sometimes called canal rays), first discovered in 1886 by Eugen Goldstein and soon thereafter recognized as beams of positive ions. As a student in the laboratory of J.J. Thomson, Aston had learned that the gaseous element neon produced two positive rays. The ions in the heavier ray had masses about two units, or 10 percent, greater than the ions in the lighter ray. To prove that the lighter neon had a mass very close to 20 and that the heavier ray was

indeed neon and not a spurious signal of some kind, Aston had to construct an instrument that was considerably more precise than any other of the time. By 1919 he had done so and convincingly argued for the existence of neon-20 and neon-22. Information from his and other laboratories accumulated rapidly in the ensuing years, and by 1935 the principal isotopes and their relative proportions were known for all but a handful of elements.

FUNDAMENTAL TERMS AND CONCEPTS

An isotope is one of two or more species of atoms of a chemical element with the same atomic number

(same number or protons in the nucleus) and position in the periodic table and nearly identical chemical behavior but with different atomic masses and physical properties. Every chemical element has one or more isotopes.

An atom is first identified and labeled according to the number of protons in its nucleus. This atomic

number is ordinarily given the symbol Z. The great importance of the atomic number derives from the observation that all atoms with the same atomic number have nearly, if not precisely, identical chemical properties. A large collection of atoms with the same atomic number constitutes a sample of an element. A bar of pure uranium, for instance, would consist entirely of atoms with atomic number 92. The periodic table of the elements assigns one place to every atomic number, and each of these places is labeled with

the common name of the element, as, for example, calcium, radon, or uranium. Not all the atoms of an element need have the same number of neutrons in their nuclei. In fact, it is precisely the variation in the number of neutrons in the nuclei of atoms that gives rise to isotopes. Hydrogen is a case in point. It has the atomic number 1. Three nuclei with one proton are known that contain 0, 1, and 2 neutrons, respectively. The three share the place in the periodic table assigned to

atomic number 1 and hence are called isotopes (from the Greek isos, meaning "same," and topos, signifying "place") of hydrogen.

Many important properties of an isotope depend on its mass. The total number of neutrons and protons (symbol A), or mass number, of the nucleus gives approximately the mass measured on the so-called atomic- mass-unit (amu) scale. The numerical difference between the actual measured mass of an isotope and A is called the mass defect.

The specification of Z, A, and the chemical symbol (a one- or two-letter abbreviation of the element's name, say Sy) in the form A/ZSy identifies an isotope adequately for most purposes. Thus in the standard notation, 1/1H refers to the simplest isotope of hydrogen and 235/92U to an isotope of uranium widely used for nuclear power generation and nuclear weapons fabrication. (Authors who do not wish to use symbols sometimes write out the element name and mass number‹hydrogen-1 and uranium-235 in the examples above.)

The term nuclide is used to describe particular isotopes, notably in cases where the nuclear rather than the chemical properties of an atom are to be emphasized. The lexicon of isotopes includes three other frequently used terms: isotones for isotopes of different elements with the same number of neutrons; isobars for isotopes of different elements with the same mass number; and isomers for isotopes identical in all respects except for the total energy content of the nuclei.

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