Radioactivity, Radionuclides, and Radiopharmaceuticals

Basic Isotope Notation

The atom may be thought of as a collection of protons, neutrons, and electrons. The protons and neutrons are found in the nucleus, and shells of electrons orbit the nucleus with discrete energy levels. The number of neutrons is usually designated by N. The number of protons is represented by Z (also called the atomic number ). The atomic mass number, or the total number of nuclear particles, is represented by A and is simply the sum of N and Z. The symbolism used to designate atoms of a certain element having the chemical symbol X is given by . For example, the notation refers to a certain isotope of iodine. In this instance, 131 refers to the total number of protons and neutrons in the nucleus. By definition, all isotopes of a given element have the same number of protons and differ only in the number of neutrons. For example, all isotopes of iodine have 53 protons.

Nuclear Stability and Decay

A given element may have many isotopes, and some of these isotopes have unstable nuclear configurations of protons and neutrons. These isotopes often seek greater stability by decay or disintegration of the nucleus to a more stable form. Of the known stable nuclides, most have even numbers of neutrons and protons. Nuclides with odd numbers of neutrons and protons are usually unstable. Nuclear instability may result from either neutron or proton excess. Nuclear decay may involve a simple release of energy from the nucleus or may actually cause a change in the number of protons or neutrons within the nucleus. When decay involves a change in the number of protons, there is a change of element. This is termed a transmutation. Isotopes attempting to reach stability by emitting radiation are radionuclides.

Several mechanisms of decay achieve stability. One of these is alpha-particle emission. In this case, an alpha (α) particle, consisting of two protons and two neutrons, is released from the nucleus, with a resulting decrease in the atomic mass number ( A ) by four and reduction of both Z and N by two. The mass of the released alpha particles is so great that they travel only a few centimeters in air and are unable to penetrate even thin paper. These properties cause alpha-particle emitters to be essentially useless for imaging purposes.

Beta-particle emission is another process for achieving stability and is found primarily in nuclides with a neutron excess. In this case, a beta (β−) particle (electron) is emitted from the nucleus accompanied by an antineutrino; as a result, one of the neutrons may be thought of as being transformed into a proton, which remains in the nucleus. Thus, beta-particle emission decreases the number of neutrons ( N ) by one and increases the number of protons ( Z ) by one, so that A remains unchanged ( Fig. 1.1 ). When Z is increased, the arrow in the decay scheme shown in Fig. 1.1 points toward the right, and the downward direction indicates a more stable state. The energy spectrum of beta-particle emission ranges from a certain maximum down to zero; the mean energy of the spectrum is about one-third of the maximum. A 2-MeV beta particle has a range of about 1 cm in soft tissue and is therefore not useful for imaging purposes.

Electron capture occurs in a neutron-deficient nuclide when one of the inner orbital electrons is captured by a proton in the nucleus, forming a neutron and a neutrino. This can occur when not enough energy is available for positron emission, and electron capture is therefore an alternative to positron decay. Because a nuclear proton is essentially changed to a neutron, N increases by one, and Z decreases by one; therefore, A remains unchanged (see Fig. 1.1 ). Electron capture may be accompanied by gamma emission and is always accompanied by characteristic radiation, either of which may be used in imaging.

If, in any of these attempts at stabilization, the nucleus still has excess energy, it may be emitted as nonparticulate radiation, with Z and N remaining the same. Any process in which energy is given off as gamma rays and in which the numbers of protons and neutrons are not changed is called isomeric transition (see Fig. 1.1 ). An alternative to isomeric transition is internal conversion. In internal conversion, the excess energy of the nucleus is transmitted to one of the orbital electrons; this electron may be ejected from the atom, which is followed by characteristic radiation when the electron is replaced. This process usually competes with gamma-ray emission and can occur only if the amount of energy given to the orbital electron exceeds the binding energy of that electron in its orbit.

The ratio of internal conversion electrons to gamma-ray emissions for a particular radioisotope is designated by the symbol α. (This should not be confused with the symbol for an alpha particle.) For an isotope such as technetium-99m ( ^99m Tc), α is low, indicating that most emissions occur as gamma rays with little internal conversion. A low conversion ratio is preferable for in vivo usage because it implies a greater number of gamma emissions for imaging and a reduced number of conversion electrons, which are absorbed by the body and thus add to the patient's radiation dose.

In many instances, a gamma-ray photon is emitted almost instantaneously after particulate decay. If there is a measurable delay in the emission of the gamma-ray photon and the resulting decay process is an isomeric transition, this intermediate excited state of the isotope is referred to as metastable. The most well-known metastable isotope is ^99m Tc (the m refers to metastable). This isotope decays by isomeric transition to a more stable state, as indicated in Fig. 1.2 . In the decay scheme, the arrows point straight down, showing that there is no change in Z. Also, ^99m Tc may decay by one of several routes of gamma-ray emission.

In cases in which there are too many protons in the nucleus (a neutron-deficient nuclide), decay may proceed in such a manner that a proton may be thought of as being converted into a neutron. This results in positron (β ⁺ ) emission , which is always accompanied by a neutrino. This obviously increases N by one and decreases Z by one, again leaving A unchanged (see Fig. 1.1 ). The downward arrow in the decay scheme again indicates a more stable state, and its leftward direction indicates that Z is decreased. Positron emission cannot occur unless at least 1.02 MeV of energy is available to the nucleus.

When a positron is emitted, it travels for a short distance from its site of origin, gradually losing energy to the tissue through which it moves. When most of its kinetic energy has been lost, the positron reacts with a resident electron in an annihilation reaction. This reaction generates two 511-keV gamma photons, which are emitted in opposite directions at about (but not exactly) 180 degrees from each other ( Fig. 1.3 ).

Radionuclide Production

Most radioactive material that does not occur naturally can be produced by particulate bombardment or nuclear fission. Both methods alter the neutron-to-proton ratio in the nucleus to produce an unstable isotope. Bombardment essentially consists of the irradiation of the nuclei of selected target elements with neutrons in a nuclear reactor or with charged particles (alpha particles, protons, or deuterons) from a cyclotron. Bombardment reactions may be summarized by equations in which the target element and bombarding particle are listed on the left side of the equation and the product and any accompanying particulate or gamma emissions are indicated on the right. For example,

These equations may be further abbreviated using parenthetical notation. The molybdenum reaction presented previously is thus represented as ⁹⁸ Mo ( n, γ) ⁹⁹ Mo. The target and product are noted on the outside of the parentheses, which contain the bombarding particle on the left and any subsequent emissions on the right.

Once bombardment is completed, the daughter isotope must be physically separated from any remaining and unchanged target nuclei, as well as from any target contaminants. Thus, it is obvious that the completeness of this final separation process and the initial elemental purity of the target are vital factors in obtaining a product of high specific activity. Because cyclotron isotope production almost always involves a transmutation (change of Z ) from one element to another, this process aids greatly in the separation of the radionuclides to obtain carrier-free isotopes (i.e., isotopes that have none of the stable element accompanying them). Radionuclides made by neutron bombardment, which does not result in a change of elemental species (e.g., ⁹⁸ Mo [ n, γ] ⁹⁹ Mo), are not carrier free because the chemical properties of the products are identical, and thus radionuclides are not as easily separated.

Fission isotopes are simply the daughter products of nuclear fission of uranium-235 ( ²³⁵ U) or plutonium-239 ( ²³⁹ Pu) in a reactor and represent a multitude of radioactive materials, with atomic numbers in the range of roughly half that of ²³⁵ U. These include iodine-131 ( ¹³¹ I), xenon-133 ( ¹³³ Xe), strontium-90 ( ⁹⁰ Sr), molybdenum-99 ( ⁹⁹ Mo), and cesium-137 ( ¹³⁷ Cs), among others. Because many of these isotopes are present together in the fission products, the desired isotope must be carefully isolated to exclude as many contaminants as possible. Although this is sometimes difficult, many carrier-free isotopes are produced in this manner.

Neutron bombardment and nuclear fission almost always produce isotopes with neutron excess, which decay by beta emission. Some isotopes, such as ⁹⁹ Mo, may be produced by either method. Cyclotron-produced isotopes are usually neutron deficient and decay by electron capture or positron emission. Some common examples of cyclotron-produced isotopes include iodine-123 ( ¹²³ I), fluorine-18 ( ¹⁸ F), gallium-67 ( ⁶⁷ Ga), indium-111 ( ¹¹¹ In), and thallium-201 ( ²⁰¹ Tl). In general, cyclotron-generated radionuclides are more expensive than are those produced by neutron bombardment or fission.

Positron-emitting radionuclides are most commonly produced in cyclotrons by charged-particle bombardment of a stable element with protons, deuterons, or helium nuclei. The produced radionuclides have an excess of protons and decay by the emission of positrons.

Radioactive Decay

The amount of radioactivity present (the number of disintegrations per second) is referred to as activity. In the past, the unit of radioactivity has been the curie (Ci), which is 3.7 × 10 ¹⁰ disintegrations per second. Because the curie is an inconvenient unit, it has been largely replaced by an international unit called a becquerel (Bq), which is 1 disintegration per second. Conversion tables are found in Appendixes B.1 and B.2 . Specific activity refers to the activity per unit mass of material (mCi/g or Bq/g). For a carrier-free isotope, the longer the half-life of the isotope, the lower is its specific activity.

Radionuclides decay in an exponential fashion, and the term half-life is often used casually to characterize decay. Half-life usually refers to the physical half-life, which is the amount of time necessary for a radionuclide to be reduced to half of its existing activity. The physical half-life ( T _p ) is equal to 0.693/λ, where λ is the decay constant. Thus, λ and the physical half-life have characteristic values for each radioactive nuclide. Decay tables for various radionuclides are presented in Appendix C .

A formula that the nuclear medicine physician should be familiar with is the following:

This formula can be used to find the activity ( A ) of a particular radioisotope present at a given time ( t ) and having started with activity ( A ₀ ) at time 0. For instance, if you had 5 mCi (185 MBq) of ^99m Tc at 9:00 a.m. today, how much would remain at 9:00 a.m. tomorrow? In this case, T _p of ^99m Tc is 6 hours, t is 24 hours, and e is a mathematical constant. Thus,

Thus, after 24 hours, the amount of ^99m Tc remaining is 0.31 mCi (11 MBq).

In addition to the physical half-life or physical decay of a radionuclide, two other half-life terms are commonly used. Biologic half-life refers to the time it takes an organism to eliminate half of an administered compound or chemical on a strictly biologic basis. Thus, if a stable chemical compound were given to a person, and half of it were eliminated by the body (perhaps in the urine) within 3 hours, the biologic half-life would be 3 hours. The effective half-life incorporates both the physical and biologic half-lives. Therefore, when speaking of the effective half-life of a particular radiopharmaceutical in humans, one needs to know the physical half-life of the radioisotope used as a tag or label, as well as the biologic half-life of the tagged compound. If these are known, the following formula can be used to calculate the effective half-life:

where

If the biologic half-life is 3 hours and the physical half-life is 6 hours, then the effective half-life is 2 hours. Note that the effective half-life is always shorter than either the physical or biologic half-life.

Radionuclide Generator Systems

A number of radionuclides of interest in nuclear medicine are short-lived isotopes that emit only gamma rays and decay by isomeric transition. Because it is often impractical for an imaging laboratory to be located near a reactor or a cyclotron, generator systems that permit on-site availability of these isotopes have achieved wide use. Some isotopes available from generators include technetium-99m, indium-113m ( ^113m In), krypton-81m ( ^81m Kr), rubidium-82 ( ⁸² Rb), strontium-87m ( ^87m Sr), and gallium-68 ( ⁶⁸ Ga).

Inside the most common generator ( ⁹⁹ Mo- ^99m Tc), a radionuclide “parent” with a relatively long half-life is firmly affixed to an ion exchange column. A ⁹⁹ Mo- ^99m Tc generator consists of an alumina column on which ⁹⁹ Mo is bound. The parent isotope (67-hour half-life) decays to its radioactive daughter, ^99m Tc, which is a different element with a shorter half-life (6 hours). Because the daughter is only loosely bound on the column, it may be removed, or washed off, with an elution liquid such as normal (0.9%) saline. Wet and dry ⁹⁹ Mo- ^99m Tc generator systems are available and differ only slightly. A wet system (most common in commercial radiopharmacies) has a saline reservoir and a vacuum vial that draws saline across the column. With a dry system (most common in imaging clinics), a specific amount of saline in a vial is placed on the generator entry port and drawn across by a vacuum vial ( Fig. 1.4 ).

After the daughter is separated from the column, the buildup process is begun again by the residual parent isotope. Uncommonly, some of the parent isotope ( ⁹⁹ Mo) or alumina is removed from the column during elution and appears in the eluate containing the daughter isotope. This is termed breakthrough .

To make efficient use of a generator, elution times should be spaced appropriately to allow for reaccumulation of the daughter isotope on the column. The short-lived daughter reaches maximum activity when the rate of decay of the daughter equals its rate of production. At this equilibrium point, for instance, the amount of daughter is slightly greater than the activity of the parent ( Fig. 1.5 ). When the parent isotope has a half-life somewhat greater than that of the daughter, the equilibrium attained is said to be a transient equilibrium. In the case of a ⁹⁹ Mo- ^99m Tc generator, because 12% of ⁹⁹ Mo decays directly to ⁹⁹ Tc without producing ^99m Tc, the activity of ^99m Tc in the generator only reaches 97% of the ⁹⁹ Mo activity.

Most generators used in hospitals have ⁹⁹ Mo activity levels of about 1 to 19 Ci (3.7 to 70.3 GBq). The amount of ^99m Tc in the generator reaches about half the theoretical maximum in one half-life (6 hours). It reaches about three-fourths of the theoretical maximum in about two half-lives, and so on (see Appendix C.1 ). This indicates that if one elutes all of the ^99m Tc daughter from a ⁹⁹ Mo generator, 24 hours later (four half-lives), the amount of ^99m Tc present in the generator will have returned to about 95% of the theoretical maximum.

Other, much less common photon-emitting radionuclide generator systems include rubidium-81 ( ⁸¹ Rb) (4.5 hours)/ ^81m Kr (13 seconds), tin-13 ( ¹¹³ Sn) (115 days)/ ^113m In (1.7 hours), yttrium-87 ( ⁸⁷ Y) (3.3 days)/ ^87m Sr (2.8 hours), and tellurium-132 ( ¹³² Te) (3.2 days)/ ¹³² I (2.3 hours). Although generator systems are most often used to produce photon-emitting radionuclides, certain generators can produce positron emitters. These include strontium-82 ( ⁸² Sr) (25 days)/ ⁸² Rb (1.3 minutes). ⁸² Rb is a potassium analog and can be used for myocardial perfusion imaging using positron emission tomography (PET). Gallium-68 (68 minutes) is another positron emitter that can be produced from a germanium-68 ( ⁶⁸ Ge) (271 days) generator.

Radionuclides and Radiopharmaceuticals for Imaging

In evaluating the choice of a radionuclide to be used in the nuclear medicine laboratory, the following characteristics are desirable:

• Minimum of particulate emission

• Primary photon energy between 50 and 500 keV

• Physical half-life greater than the time required to prepare material for injection

• Effective half-life longer than the examination time

• Suitable chemical form and reactivity

• Low toxicity

• Stability or near-stability of the product

The radionuclides most commonly used are shown in Tables 1.1 and 1.2 . A radionuclide that has desirable imaging properties can usually be used to make a variety of radiopharmaceuticals. This is done by coupling the radionuclide with various stable compounds that are localized by organs or disease states. Many radionuclides are radiopharmaceuticals in their own right and can be administered without alteration to obtain useful images. Commonly used imaging radiopharmaceuticals are shown in Table 1.3 . The biologic behavior of most of these radionuclides can be markedly altered by a combination with additional substances to form other radiopharmaceuticals.

TABLE 1.2

Characteristics of Common Positron Emission Tomography (PET) Radionuclides

Nuclide (Decay Product)	Physical Half-Life	Decay Mode	Maximal and Average Positron Energy (keV)	Maximum and Mean Range in Water (mm)	Production Reaction
Carbon-11 (Boron-11)	20.3 min	99.8% positron 0.2% electron capture	960, 385	4.1, 1.1	14 N(p,alpha) 11 C *
Nitrogen-13 (Carbon-13)	10 min	100% positron	1198, 491	5.1, 1.4	16 O(p,alpha) 13 N; 13 C(p,n) 13 N
Oxygen-15 (Nitrogen-15)	124 s	99.9% positron	1730, 735	7.3, 1.5	15 N(p,n) 15 O; 14 N(d,n) 15 O
Fluorine-18 (Oxygen-18)	110 min	97% positron 3% electron capture	634, 250	2.4, 1.0	18 O(p,n) 18 F; 20 Ne(d,alpha) 18 F; 16 O( 3 He,alpha) 18 F
Gallium-68 (Zinc-68)	68 min	100% positron	1899	8.9, 2.9	68 Ge generator ( 271 days)
Rubidium-82 (Krypton-82)	75 s	96% positron 4% electron capture	3150, 1385	14.1, 5.9	82 Sr generator ( 25.3 days)

* This symbolism means that a proton is accelerated into an atom of nitrogen-14, causing the ejection of an alpha particle from the nucleus to produce an atom of carbon-11.

Mechanisms of localization for some of these radiopharmaceuticals are listed in Table 1.4 . The various radiopharmaceuticals used in imaging procedures are additionally discussed in the appropriate chapters. Dosimetry and protocols for the various radionuclides are presented in Appendix E . Issues related to pediatric dose and pregnancy and breastfeeding are in Appendixes D and G .

Although the localizing properties of radiopharmaceuticals are generally sufficient to obtain adequate diagnostic images, the localizing mechanisms may be altered by various conditions in an individual patient, including the administration of other medications.

Single Photon

Technetium-99m

Technetium-99m fulfills many of the criteria of an ideal radionuclide and is used in more than 80% of nuclear imaging procedures in the United States. It has no particulate emission, a 6-hour half-life, and a predominant (98%) 140-keV photon. The decay mode is 88% isomeric transition and only a small amount (12%) of internal conversion.

Technetium-99m is obtained by separating it from the parent ⁹⁹ Mo (67-hour half-life) in a generator system. Molybdenum-99 for generators is generally produced by neutron irradiation of ⁹⁸ Mo or by chemical separation of ²³⁵ U fission products. In the latter case, ⁹⁹ Mo is nearly carrier free and has a high specific activity. In the alumina generator system, the molybdenum activity is absorbed on an alumina column. By passing physiologic saline over the column, ^99m Tc is eluted or washed off as sodium pertechnetate (Na ^99m TcO ₄ –).

Technetium can exist in a variety of valence states, ranging from −1 to +7. When eluted from an alumina column generator, ^99m Tc is present primarily as heptavalent (+7) pertechnetate (TcO ₄ –). In the preparation of radiopharmaceuticals, ^99m Tc pertechnetate can be reduced from +7 to a lower valence state, usually +4, to permit the labeling of various chelates. This is generally accomplished with stannous (tin) ions.

As pertechnetate, the technetium ion is a singly charged anion and is similar in size to the iodide ion. After intravenous injection, ^99m Tc pertechnetate is loosely bound to protein and rapidly leaves the plasma compartment. More than half leaves the plasma within several minutes and is distributed in the extracellular fluid. It rapidly concentrates in the salivary glands, choroid plexus, thyroid gland, gastric mucosa, and functioning breast tissue; during pregnancy, it crosses the placenta.

Excretion is by the gastrointestinal and renal routes. Although ^99m Tc pertechnetate is excreted by glomerular filtration, it is partially reabsorbed by the renal tubules; as a result, only 30% is eliminated in the urine during the first day. The ion is also secreted directly into the stomach and colon, with a much smaller amount coming from the small bowel. The colon is the critical organ and receives about 1 to 2 rad/10 mCi (0.04 mGy/MBq) of ^99m Tc pertechnetate administered. The biodistribution of ^99m Tc pertechnetate is shown in Fig. 1.6 . The principal emission (140-keV photon) of ^99m Tc has a half-value layer (HVL) of 0.028 cm in lead and 4.5 cm in water. Because tissue is close to water in terms of attenuation characteristics, it is clear that about 2 inches of tissue between the radionuclide and the detector removes about half of the photons of interest, and 4 inches removes about three-fourths.

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