An Introduction to Nuclear Medicine

Brian Lentle and Anna Celler Introduction

Nuclear medicine is defined as that medical specialty concerned with the use of unsealed sources of radiation in the diagnosis and treatment of disease.

Disease usually begins as disordered function. While an exception to this might be trauma, many accidents also may be due to altered behavior. Thus altered function often anticipates structural or morphological change by months or even years. Other techniques used in diagnostic imaging (e.g., radiography, computed tomography [CT] and magnetic resonance imaging [MRI]) largely focus on the identification of disordered structure although with the emergence of advanced MRI methods this is beginning to change. The power of nuclear medicine in clinical diagnosis rests with its ability to detect altered function with great sensitivity. For this reason nuclear medicine has contributed not only to clinical diagnosis but, to a degree unmatched by other imaging methods, to an understanding of disease mechanisms.

History

Modern clinical radiology began with one seminal event, namely Wilhelm Röntgen's discovery of X-rays in November 1895. Nuclear medicine had not one but many parents. Bequerel discovered radioactivity in early 1896. Both of these discoveries were serendipitous. Röntgen, a German physicist, was experimenting in his laboratory in Würzburg. While working with cathode-ray tubes in a darkened room he noticed, by chance, fluorescence at a distance. He went on to discover that this fluorescence was caused by penetrating, but hitherto undiscovered, radiations from the cathode-ray tubes. He called these X-rays, using the algebraic symbol "x" for an unknown. Before the end of that year Röntgen had used the new rays to image the internal structure of the body—the bones of his wife's hand.

Subsequently Henri Becquerel (Fig. 1) discovered natural radioactivity in February 1896. The story has it that he placed lumps of pitchblende on sealed photographic film in sunlight, intent on finding out if the rays of the sun induced any penetrating fluorescence in the mineral. By chance, on developing the film after a cloudy day he was surprised to find as much blackening of the photographic emulsion as had occurred in bright sunlight. He realized that the pitchblende itself was a source of the energetic rays.

Later Mme. (Dr.) Marie and Dr. Pierre Curie working in Paris described natural radioactivity and discovered radium. Subsequently Mme. (Dr.) Irène Curie was to observe the artificial induction of radioactivity. Rutherford, a British-educated, New Zealand physicist working at McGill University in Montreal went on to discover the structure of the atom. All won Nobel prizes—Becquerel and Curie jointly.

Nuclear Medicine, edited by William D. Leslie and I. David Greenberg. ©2003 Landes Bioscience.

Figure 1. A stamp commemorating Becquerel's discovery of radioactivity for which he received a Nobel Prize.

Another important insight came when a Hungarian scientist—George de Hevesy (a former student of Rutherford)—first used the tracer principle (Fig. 2). He experimented with a plant having its roots in a water bath containing a radioactive isotope of lead. Hevesy was able to follow the rate of passage of the tracer through

Figure 2. A stamp celebrating the anniversary of the Nobel Prize awarded to de Hevesy for the discovery of the tracer principle.

the stem of the plant with an instrument capable of detecting and measuring radioactivity. This use of radioactive atoms, present in minute amounts but acting as a marker of other, non-radioactive atoms came to be called the tracer principle. It only required that Hevesy's insight be translated to people instead of plants, and for the tracer to be administered by injection instead of through a plant's root system, for the power of nuclear medicine to become clear.

d Without a capacity to image the distribution of radiotracers in the body, however, there might be little to remark upon concerning the importance of nuclear medicine. Dr. Benedict Cassen developed the first rectilinear scanner to image tracers by virtue of the gamma rays they emit. This was followed by the development of the gamma camera, able to image both static and changing distributions of radioactive tracers in the body, by Dr. Hal Anger. He, Dr. David Kuhl and others went on to develop the concept of tomographic sectional imaging in nuclear medicine.

Nuclear medicine, while beginning in the late nineteenth century, gained momentum through the twentieth. Medicine in the twenty-first century will continue to be fundamentally changed by the insights it provides.

Comparative imaging and the Role of Nuclear Medicine

Classical radiology had been rooted in studies of structure. That is changing as physiological images and sometimes measurements are being made with CT and, especially, functional MRI and spectroscopy. Nevertheless, from first principles it will be difficult to match the power of nuclear medicine in, for example, detecting receptor binding.

Another decisive advantage of nuclear medicine is its capacity to be used in whole body imaging. The idea of whole body MRI "screening" has been mooted but its value is speculative and it would be expensive. In contrast, nuclear medicine body imaging is unsurpassed in the search for disease not causing local symptoms, such as metastatic tumor spread or occult infections.

As we have seen, the first technique which allowed us to "see" the inside of the human body was X-ray imaging. Very soon, however, it was followed by other techniques such as nuclear medicine, ultrasound (US), CT and, more recently, MRI. In order to realize the possibilities and limitations of each technique and to better understand their place in the diagnostic process it is important to consider the physical process that each modality employs. In differing degrees most methods are capable of anatomical and functional imaging and almost all techniques can examine both when special contrast agents or other modifications are used.

Attenuation of electromagnetic radiation (which depends on the electron density of the material) is the physical principle used in X-ray imaging or CT. The resulting images represent differences in transmission of the X-rays (a form of electromagnetic radiation) or, indirectly, differences in their attenuation by tissues and, thereby, the anatomy of the subject. If a special contrast agent is introduced any images made will reflect the distribution of this agent and such images may depict a particular organ's function. Similarly, from the physical point of view, US measures sound wave transmission and reflection in the body and MRI is sensitive to body water contents because hydrogen atoms in water molecules are responsible for the majority of the magnetic signal detected by MRI. Again, in both situations, the images display more particularly the anatomy, not function. Recently developed functional MRI (fMRI), however, is sensitive to the flow of the blood in the body while doppler US can additionally measure the movement, for example of blood, within an imaged organ.

Nuclear medicine, by contrast, is a technique that is intrinsically functional because it measures radiation emitted by a tracer which has been introduced into a patient's body, usually by injection, and for which the location and concentration are directly related to the function of an organ. The term "nuclear medicine" encompasses several different imaging techniques ranging from positron emission tomography (PET) and single photon emission computed tomography (SPECT) through whole body planar images or "scans."

There are several ways in which the analysis of nuclear medicine data can be done ranging from a simple and qualitative visual inspection of planar images up to a full numerical and quantitative analysis of the three- or even four-dimensional (including temporal) data sets. Creation of these quantitative images is quite complex and usually requires application of several corrections to the data (attenuation, scatter, normalization, for example) as well as iterative reconstruction methods. Also the use of quantitative analytical methods usually involves kinetic modeling and sophisticated computer-based operations. The information obtained from such analyses can be directly related, however, to physiological processes and may provide a very useful and comprehensive picture of a disease. At present this type of data analysis is available mostly in centers with strong research programs because only the most advanced nuclear medicine systems using modern image reconstruction techniques are able to realize fully quantitative data. Therefore, diagnostic applications of this approach remain in development.

The relative sensitivities of PET and MRI for the detection of metabolic changes in vivo are such that PET can detect concentrations of metabolites several orders of magnitude smaller than those detectable with MRI. Thus, while functional and anatomic imaging are converging, the methods each have strengths and weaknesses which suggest that both will have a role to play in the future. Indeed there is growing interest not only in fusing anatomical and functional images but also in obtaining such images with hybrid technology combining, for example, PET and CT.

Radionuclide production

Radioactive atoms (radionuclides) are fundamental to the tracer principle. Thus their production is an important step in the clinical practice of nuclear medicine.

The radionuclides used in imaging usually emit gamma (y) rays. Occasionally a particle is emitted as well. X-rays and y-rays are both part of the electromagnetic spectrum. Visible light, radiowaves and microwaves are also part of this spectrum. However, X-rays and y-rays are of short wavelength and thus are energetic and can penetrate tissues. The penetrating power of X-rays and y-rays is a function of their energy usually measured in electron volts—the gamma rays from technetium-99m are of 140 thousand electron volts (140 keV). While y-rays are in general more energetic than X-rays the real distinction between them stems from their origins: y-rays are produced in nuclear decay processes whereas X-rays derive from orbital electron perturbations produced, for example, by electrons accelerated in an X-ray tube.

Radionuclides may be created by one or other of the following methods.

Cyclotron Irradiation

Radionuclides may be made by irradiation of stable atoms with cyclotron-accelerated particles—usually protons. This method of production is especially important for those radioactive atoms used in PET since these usually have very short half-lives and must be manufactured where they are to be used. The reaction d

Figure 3. Beta-minus decay with the emission of a y-ray (iodine-131 decays in this way).

can be represented as follows, where the oxygen atom is stable, p is the accelerated proton, n is the neutron produced and fluorine-18 is the resulting tracer (half-life about 2 hours):

In this reaction oxygen has eight protons and fluorine nine in the respective nuclei. The superscripts used throughout this volume refer to the atomic mass of the atom, essentially the sum of the protons and neutrons in the atomic nucleus since electrons and other particles have negligible mass.

Reactor Irradiation

Atomic nuclei may be made radioactive by the flux of neutrons in a nuclear reactor or from the fission of heavier atoms. Molybdenum, for example, may be made by either of the following reactions:

235U (n, fission) ^ "Mo (high specific activity)

In these reactions n stands for a neutron and y for a gamma ray. Specific activity is a measure of the fraction of radioactive atoms present of the total in the sample— important to consider in the preparation of some radiopharmaceuticals.

Reactor produced atoms are often rich in neutrons and thus decay by |3- emissions (e.g., iodine-131) (Fig. 3). |3- particles (energetic electrons) give large local radiation doses which may be destructive. This may make them important in therapy as in the use of radioactive iodine to treat Graves' disease and thyroid cancer.

Generator Production

A common strategy in nuclear medicine practice is to take delivery, at a hospital or clinic, of a generator containing a long-lived precursor of a short-lived daughter isotope. The precursor may be made in either a reactor or cyclotron. Molybdenum-99/technetium-99m generators (Fig. 4) are very widely used in nuclear medicine, the molybdenum most often being reactor produced. Technetium-99m has many useful features (short half-life, no particulate emissions to cause large radiation exposures to patients and a Y-ray energy ideal for gamma-camera detection) and is

Parent

Parent

Ground state

Figure 4. A section through a generator (diagrammatic). Saline is introduced through the inlet needle and extracted at the outlet needle containing technetium-99m as sodium pertechnetate. The technetium-99m is not absorbed on the aluminum oxide as is the molybdenum-99.

more widely used than any other radionuclide at present. Yet with a half-life of about six hours it would not be readily available on the scale on which it is used were it not for its availability from a generator. The generator contains a long-lived molybdenum-99 parent absorbed onto a column and, as this radionuclide decays, technetium (which being different chemically is not so absorbed) is eluted (milked) from the column in the generator on a daily or twice-daily basis. The molybdenum decays as follows:

and the technetium used in preparing the radiotracer then decays as follows (Fig. 5):

99mTc ^ 99Tc + Y with the y-rays being used for imaging.

Figure 5. Decay of technetium-99m. Radionuclide Decay

Some nuclei are unstable and decay at a rate described by the half-life (the time taken for 50% of the nuclei of a given radioactive sample to decay). The life expectancy of an individual atom is impossible to predict but in the large numbers in which they are produced the whole-population characteristic half-life can be described by bulk averaging. Radioactive instability is related to the excess of energy contained in a given "excited" nucleus and often results from an imbalance of the numbers of protons and neutrons in the nucleus. Radioactive atoms decay by a number of processes each with different implications for nuclear medicine practice. Decay processes may be classified according to whether in the atoms in question the imbalance leads to a neutron-rich nucleus (usually reactor produced) or proton-rich nucleus (usually accelerator produced). The commoner forms of decay are described. Half-lives and principal emissions from common radionuclides are summarized in Appendix I.

Figure 5. Decay of technetium-99m. Radionuclide Decay

Some nuclei are unstable and decay at a rate described by the half-life (the time taken for 50% of the nuclei of a given radioactive sample to decay). The life expectancy of an individual atom is impossible to predict but in the large numbers in which they are produced the whole-population characteristic half-life can be described by bulk averaging. Radioactive instability is related to the excess of energy contained in a given "excited" nucleus and often results from an imbalance of the numbers of protons and neutrons in the nucleus. Radioactive atoms decay by a number of processes each with different implications for nuclear medicine practice. Decay processes may be classified according to whether in the atoms in question the imbalance leads to a neutron-rich nucleus (usually reactor produced) or proton-rich nucleus (usually accelerator produced). The commoner forms of decay are described. Half-lives and principal emissions from common radionuclides are summarized in Appendix I.

Electron (or Beta-) Particle Emission (Fig. 3)

Neutron-rich atoms decay by the transformation of a neutron into a proton and electron. The proton remains in the nucleus but the electron is emitted, and for historical reasons, it is in this context called a [3-minus particle: n ^ p + e ~ + v where the n is a neutron, p a proton, e' the negative electron (beta particle) and v an antineutrino (an undetectable and nearly mass-less particle). In this reaction the daughter atom has the same mass number as the parent but an increase in one of the atomic number because of the increase in number of protons in the nucleus.

Isomeric Transition (Gamma Decay) (Fig. 5)

This method involves an internal rearrangement of the nuclear structure with minimal change in atomic weight. However, an alteration in the energy state of the nucleus results in the emission of y-rays. Such y-rays are very energetic forms of electromagnetic radiation, like light, and lose little of their energy in the body. Thus little radiation damage results to the tissues while the gamma rays are well-suited to imaging the distribution in the body of the physiological molecule-of-interest to which they are attached. For such reasons technetium-99m which decays by this mechanism is widely used in nuclear medicine, the decay schematic being as follows: 99mTc ^ 99Tc + y

Electron Capture

If a nucleus is not sufficiently energetic to decay by positron emission (see below) it may capture an orbital electron. A proton is then transformed into a neutron and a neutrino emitted. Since a vacancy is created in the inner electron shell, this is filled from outer rings and a succession of so-called characteristic X-rays result (characteristic because of their specific and recognizable energies). Examples used in nuclear medicine are indium-111 and iodine-123. The decay schematic is as follows:

Internal Conversion

This type of decay occurs in parallel to y-decay. It is the result of an energetic radioactive nucleus transferring its energy to an orbital electron which is ejected, rather than a y-ray. The result is again characteristic X-rays (as the orbital vacancy is filled) and the electron (called an Auger electron) of discrete energy. This process is particularly important in calculations of radiation doses resulting from radioactive decay.

Positron (Beta+) Emission

Positrons (or positive electrons) are an example of anti-matter so beloved of science fiction writers. However, positrons have a very important role in nuclear medicine. They result from the decay of proton-rich nuclei. It so happens that the only externally detectable isotopes of carbon, hydrogen, oxygen and nitrogen (which make up a major part of bodily tissues) are carbon-11, oxygen-13 and nitrogen-15, all proton rich. All three decay by positron-emission albeit with very short half-lives. Add in fluorine-18, which can substitute for hydroxyl groups and which is also a positron-emitting radionuclide, and it is apparent that detection of positron emissions might be a very powerful tool for studying disease. Indeed positrons might also be used to study the mechanisms of disease and the behavior and localization of important molecules in the body.

Positrons do not decay themselves but are extremely short-lived. When they lose their kinetic energy after collision(s) with electrons they finally meet a negative electron and the particles mutually annihilate. The energy associated with their rest mass appears as two high-energy electromagnetic photons (each of an energy of 0.511

Figure 6. Positron decay and the principle of positron emission tomography. The positron, after a short path and scattering off negative electrons, interacts with such an electron. As both annihilate, their rest mass results in two photons detected as coincidental events in the detector ring.

MeV) propagated in nearly opposite directions—following Einstein's famous equation describing the equivalence of mass and energy: E = mc2. Their detection is central to the technique of PET (Fig. 6), but may also be done with gamma cameras.

Alpha-Particle Decay

Alpha (a) particles (consisting of two protons and two neutrons - the nuclei of helium atoms) usually result from the decay of heavier nuclei. Their large mass and short range make them virtually undetectable outside the body as they are usually absorbed in close proximity to the site at which they decay. This mechanism of decay is not used, for that reason, in radionuclide imaging. On the other hand, the large local radiation damage produced in tissues makes molecules labeled with a-particles of great potential interest in the treatment of cancers.

Detection Systems

We have seen that the strength of nuclear medicine lies in the use of radioactive atoms to detect disease, analyze physiological processes (the tracer principle), treat cancers, and a myriad of other applications. It remains, therefore, for us to explore the systems used to detect and localize high-energy radiations. The machines in use

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