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Essentials of Nuclear Medicine and
Molecular Imaging
7th Edition

Fred A. Mettler, Jr., MD, MPH

Emeritus Professor
Department of Radiology
University of New Mexico
School of Medicine
Health Sciences Center
Albuquerque, New Mexico

Milton J. Guiberteau, MD, FACR, FACNM

Professor
Department of Radiology
Baylor College of Medicine
Texas Medical Center
Houston, Texas

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1600 John F. Kennedy Blvd.
Ste 1600
Philadelphia, PA 19103-2899

ESSENTIALS OF NUCLEAR MEDICINE AND MOLECULAR IMAGING: ISBN: 978-0-323-48319-3

SEVENTH EDITION

Copyright © 2019 by Elsevier, Inc. All rights reserved.

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Notices

Knowledge and best practice in this field are constantly changing. As new research and experience broaden
our understanding, changes in research methods, professional practices, or medical treatment may become
necessary.
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and
using any information, methods, compounds, or experiments described herein. In using such information or
methods, they should be mindful of their own safety and the safety of others, including parties for whom they
have a professional responsibility.
With respect to any drug or pharmaceutical products identified, readers are advised to check the most
current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be
administered, to verify the recommended dose or formula, the method and duration of administration, and
contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of
their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient,
and to take all appropriate safety precautions.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors assume any
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 To those who spend their time teaching residents and
to the families and spouses who support them, especially our own.

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Preface

Six years have passed since the previous edition of our book, the suggested readings and the format for self-assessment.
and 38 years since the first edition. Although nuclear medi- We purposely elected to express radiotracer activities and
cine has continued to evolve with innovative radiotracers doses in both conventional and SI formats, because many
and new technologies (including hybrid imaging tech- physicians still use conventional units in some or all aspects
niques), its use has been replaced by CT, MRI, and ultra- of their practices. In the sixth edition, 40% of the images
sound for a number of indications. In this context, it is were new; the vast majority of these images remain relevant,
critical for practitioners to know the current indications, although new ones have been added where necessary.
benefits, and limitations of our procedures and to combine A primary goal of our long partnership as authors of this
this with additional noninterpretative skills for optimal book has been to create a clear and readable presentation of
patient outcomes. the essentials of nuclear medicine practice rather than accu-
In this seventh edition, we have added new material on a mulate a collection of chapters by multiple authors with
wide range of topics, including solid-state detectors, demen- varying teaching perspectives and writing styles. Our readers
tia evaluation, myocardial perfusion imaging and quantita- appear to have appreciated this over the years. We hope we
tion protocols, advances in radiopharmaceuticals, use of have succeeded with this edition and encourage you to
PET/CT for theranostics, initial therapy selection, treat- forward any suggestions for future editions to us. We wish
ment response evaluation and change in management when you the best of luck and satisfaction in your career.
needed, pulmonary embolism evaluation during pregnancy,
SNMMI practice guidelines and appropriateness recom- Fred A. Mettler, Jr.
mendations, new ICRP/ICRU dosimetry values, and radia- Milton (Mickey) J. Guiberteau
tion biology. Pearls and Pitfalls have been updated, as have

vi

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Acknowledgments

We would like to recognize the many residents, technolo-

gists, and others who provided suggestions, as well as a
number of our colleagues who provided images, background
material, and comments. We also thank RuthAnne Bump
for her help with the illustrations.

vii

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1
Radioactivity, Radionuclides, and
Radiopharmaceuticals
CHAPTER OUTLINE

Basic Isotope Notation Investigational Radiopharmaceuticals

Nuclear Stability and Decay Radiopharmacy Quality Control
Radionuclide Production Generator and Radionuclide Purity
Radioactive Decay Radiochemical Labeling
Radionuclide Generator Systems Unsealed Radionuclides Used for Therapy
Radionuclides and Radiopharmaceuticals for Imaging Phosphorus-32, Yttrium-90, and Gold-198
Single Photon Iodine-131
Positron Emitters Strontium-89, Samarium-153, Rhenium-186, and
Radium-223
Biologic Agents and Nanoparticles
Adverse Reactions

BASIC ISOTOPE NOTATION Of the known stable nuclides, most have even numbers of
neutrons and protons. Nuclides with odd numbers of neu-
The atom may be thought of as a collection of protons, trons and protons are usually unstable. Nuclear instability
neutrons, and electrons. The protons and neutrons are may result from either neutron or proton excess. Nuclear
found in the nucleus, and shells of electrons orbit the decay may involve a simple release of energy from the nucleus
nucleus with discrete energy levels. The number of neutrons or may actually cause a change in the number of protons or
is usually designated by N. The number of protons is rep- neutrons within the nucleus. When decay involves a change
resented by Z (also called the atomic number). The atomic in the number of protons, there is a change of element. This
mass number, or the total number of nuclear particles, is is termed a transmutation. Isotopes attempting to reach stabil-
represented by A and is simply the sum of N and Z. The ity by emitting radiation are radionuclides.
symbolism used to designate atoms of a certain element Several mechanisms of decay achieve stability. One of
having the chemical symbol X is given by ZA X N . For example, these is alpha-particle emission. In this case, an alpha (α)
the notation 131
53 I78 refers to a certain isotope of iodine. In particle, consisting of two protons and two neutrons, is
this instance, 131 refers to the total number of protons and released from the nucleus, with a resulting decrease in the
neutrons in the nucleus. By definition, all isotopes of a given atomic mass number (A) by four and reduction of both Z
element have the same number of protons and differ only and N by two. The mass of the released alpha particles is so
in the number of neutrons. For example, all isotopes of great that they travel only a few centimeters in air and are
iodine have 53 protons. unable to penetrate even thin paper. These properties cause
alpha-particle emitters to be essentially useless for imaging
Nuclear Stability and Decay purposes.
Beta-particle emission is another process for achieving
A given element may have many isotopes, and some of these stability and is found primarily in nuclides with a neutron
isotopes have unstable nuclear configurations of protons excess. In this case, a beta (β−) particle (electron) is emitted
and neutrons. These isotopes often seek greater stability by from the nucleus accompanied by an antineutrino; as a
decay or disintegration of the nucleus to a more stable form. result, one of the neutrons may be thought of as being

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2 C HA P T E R 1 Radioactivity, Radionuclides, and Radiopharmaceuticals

A A
Z
X Z
X

A A
Z+1
Y Z-1
Y
Beta particle emission Electron capture
(Z increases by 1, N decreases by 1) (Z decreases by 1, N increases by 1)

A A
Z
X Z
X

A A
Z-1
Y Z
X
Positron emission Isomeric transition
(Z decreases by 1, N increases by 1) (no change in N or Z)

• Fig. 1.1 Decay schemes of radionuclides from unstable states (top line of each diagram) to more stable
states (bottom line).

transformed into a proton, which remains in the nucleus. in which energy is given off as gamma rays and in which
Thus, beta-particle emission decreases the number of neu- the numbers of protons and neutrons are not changed is
trons (N) by one and increases the number of protons (Z) called isomeric transition (see Fig. 1.1). An alternative to
by one, so that A remains unchanged (Fig. 1.1). When Z is isomeric transition is internal conversion. In internal conver-
increased, the arrow in the decay scheme shown in Fig. 1.1 sion, the excess energy of the nucleus is transmitted to one
points toward the right, and the downward direction indi- of the orbital electrons; this electron may be ejected from
cates a more stable state. The energy spectrum of beta- the atom, which is followed by characteristic radiation when
particle emission ranges from a certain maximum down to the electron is replaced. This process usually competes with
zero; the mean energy of the spectrum is about one-third gamma-ray emission and can occur only if the amount of
of the maximum. A 2-MeV beta particle has a range of energy given to the orbital electron exceeds the binding
about 1 cm in soft tissue and is therefore not useful for energy of that electron in its orbit.
imaging purposes. The ratio of internal conversion electrons to gamma-ray
Electron capture occurs in a neutron-deficient nuclide emissions for a particular radioisotope is designated by the
when one of the inner orbital electrons is captured by a symbol α. (This should not be confused with the symbol
proton in the nucleus, forming a neutron and a neutrino. for an alpha particle.) For an isotope such as technetium-
This can occur when not enough energy is available for 99m (99mTc), α is low, indicating that most emissions occur
positron emission, and electron capture is therefore an alter- as gamma rays with little internal conversion. A low conver-
native to positron decay. Because a nuclear proton is essen- sion ratio is preferable for in vivo usage because it implies
tially changed to a neutron, N increases by one, and Z a greater number of gamma emissions for imaging and a
decreases by one; therefore, A remains unchanged (see Fig. reduced number of conversion electrons, which are absorbed
1.1). Electron capture may be accompanied by gamma by the body and thus add to the patient’s radiation dose.
emission and is always accompanied by characteristic radia- In many instances, a gamma-ray photon is emitted almost
tion, either of which may be used in imaging. instantaneously after particulate decay. If there is a measur-
If, in any of these attempts at stabilization, the nucleus able delay in the emission of the gamma-ray photon and
still has excess energy, it may be emitted as nonparticulate the resulting decay process is an isomeric transition, this
radiation, with Z and N remaining the same. Any process intermediate excited state of the isotope is referred to as

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 CHAPTER 1 Radioactivity, Radionuclides, and Radiopharmaceuticals 3

99m
142.7 keV Tc (6.03 h)

Gamma 1

140.5 keV

Gamma 2 Gamma 3

99
0 keV Tc (2.1 x 109 yr)
98.6% 1.4%

• Fig. 1.2 Decay scheme of technetium-99m.

metastable. The most well-known metastable isotope is 99mTc

(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 511 keV photons
that there is no change in Z. Also, 99mTc 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+) emis- β
sion, which is always accompanied by a neutrino. This obvi-
180 degrees / 0.25 degrees
ously increases N by one and decreases Z by one, again β
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 • Fig. 1.3 Positron Decay. After the positron (β+) is emitted from the
511-keV gamma photons, which are emitted in opposite radionuclide, it travels some distance before interacting with an elec-
directions at about (but not exactly) 180 degrees from each tron (β−) and undergoing annihilation, resulting in emission of two
511-keV photons at 180 degrees from each other.
other (Fig. 1.3).

RADIONUCLIDE PRODUCTION
bombarding particle are listed on the left side of the equa-
Most radioactive material that does not occur naturally can tion and the product and any accompanying particulate or
be produced by particulate bombardment or nuclear fission. gamma emissions are indicated on the right. For example,
Both methods alter the neutron-to-proton ratio in the
nucleus to produce an unstable isotope. Bombardment A
Z X + n (neutron ) → A +1
Z X + γ or more specifically
essentially consists of the irradiation of the nuclei of selected
42 Mo + γ
Mo + n (neutron ) → 99
98
target elements with neutrons in a nuclear reactor or with 42
charged particles (alpha particles, protons, or deuterons)
from a cyclotron. Bombardment reactions may be summa- These equations may be further abbreviated using paren-
rized by equations in which the target element and thetical notation. The molybdenum reaction presented

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4 C HA P T E R 1 Radioactivity, Radionuclides, and Radiopharmaceuticals

previously is thus represented as 98Mo (n, γ) 99Mo. The Appendixes B.1 and B.2. Specific activity refers to the activ-
target and product are noted on the outside of the paren- ity per unit mass of material (mCi/g or Bq/g). For a carrier-
theses, which contain the bombarding particle on the left free isotope, the longer the half-life of the isotope, the lower
and any subsequent emissions on the right. is its specific activity.
Once bombardment is completed, the daughter isotope Radionuclides decay in an exponential fashion, and the
must be physically separated from any remaining and term half-life is often used casually to characterize decay.
unchanged target nuclei, as well as from any target contami- Half-life usually refers to the physical half-life, which is the
nants. Thus, it is obvious that the completeness of this final amount of time necessary for a radionuclide to be reduced
separation process and the initial elemental purity of the to half of its existing activity. The physical half-life (Tp) is
target are vital factors in obtaining a product of high specific equal to 0.693/λ, where λ is the decay constant. Thus, λ
activity. Because cyclotron isotope production almost always and the physical half-life have characteristic values for each
involves a transmutation (change of Z) from one element radioactive nuclide. Decay tables for various radionuclides
to another, this process aids greatly in the separation of the are presented in Appendix C.
radionuclides to obtain carrier-free isotopes (i.e., isotopes A formula that the nuclear medicine physician should be
that have none of the stable element accompanying them). familiar with is the following:
Radionuclides made by neutron bombardment, which does
not result in a change of elemental species (e.g., 98Mo [n, γ] A = A 0e −0.693 Tp( t )
99
Mo), are not carrier free because the chemical properties
of the products are identical, and thus radionuclides are not This formula can be used to find the activity (A) of a
as easily separated. particular radioisotope present at a given time (t) and having
Fission isotopes are simply the daughter products of started with activity (A0) at time 0. For instance, if you had
nuclear fission of uranium-235 (235U) or plutonium-239 5 mCi (185 MBq) of 99mTc at 9:00 a.m. today, how much
(239Pu) in a reactor and represent a multitude of radioactive would remain at 9:00 a.m. tomorrow? In this case, Tp of
99m
materials, with atomic numbers in the range of roughly half Tc is 6 hours, t is 24 hours, and e is a mathematical
that of 235U. These include iodine-131 (131I), xenon-133 constant. Thus,
(133Xe), strontium-90 (90Sr), molybdenum-99 (99Mo), and
−0.693
cesium-137 (137Cs), among others. Because many of these (t )
isotopes are present together in the fission products, the A = A0e Tp

desired isotope must be carefully isolated to exclude as many −0.693

( 24 hours )
contaminants as possible. Although this is sometimes diffi- A = A0e 6 hours
cult, many carrier-free isotopes are produced in this manner. −0.693
( 24 hours )
Neutron bombardment and nuclear fission almost always A = 5 mCi e 6 hours

produce isotopes with neutron excess, which decay by beta

emission. Some isotopes, such as 99Mo, may be produced A = 5 mCi e −0.1155 ( 24 hours )
by either method. Cyclotron-produced isotopes are usually
neutron deficient and decay by electron capture or positron A = 5 mCi e −2.772
emission. Some common examples of cyclotron-produced
1
isotopes include iodine-123 (123I), fluorine-18 (18F),
gallium-67 (67Ga), indium-111 (111In), and thallium-201 A = 5 mCi e 2.772
(201Tl). In general, cyclotron-generated radionuclides are 1 
more expensive than are those produced by neutron bom- A = 5 mCi 
 15.99 
bardment or fission.
Positron-emitting radionuclides are most commonly A = 0.31 mCi
produced in cyclotrons by charged-particle bombardment
of a stable element with protons, deuterons, or helium Thus, after 24 hours, the amount of 99mTc remaining is
nuclei. The produced radionuclides have an excess of 0.31 mCi (11 MBq).
protons and decay by the emission of positrons. In addition to the physical half-life or physical decay of
a radionuclide, two other half-life terms are commonly
RADIOACTIVE DECAY used. Biologic half-life refers to the time it takes an organism
to eliminate half of an administered compound or chemical
The amount of radioactivity present (the number of disin- on a strictly biologic basis. Thus, if a stable chemical com-
tegrations per second) is referred to as activity. In the past, pound were given to a person, and half of it were eliminated
the unit of radioactivity has been the curie (Ci), which is by the body (perhaps in the urine) within 3 hours, the
3.7 × 1010 disintegrations per second. Because the curie is biologic half-life would be 3 hours. The effective half-life
an inconvenient unit, it has been largely replaced by an incorporates both the physical and biologic half-lives.
international unit called a becquerel (Bq), which is 1 disin- Therefore, when speaking of the effective half-life of a par-
tegration per second. Conversion tables are found in ticular radiopharmaceutical in humans, one needs to know

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 CHAPTER 1 Radioactivity, Radionuclides, and Radiopharmaceuticals 5

the physical half-life of the radioisotope used as a tag or Saline vial Vacuum vial
label, as well as the biologic half-life of the tagged com-
pound. If these are known, the following formula can be
used to calculate the effective half-life:

Te = (T p × Tb ) (T p + Tb )

where Lead

Te = effective half-life
T p = physical half-life
Tb = biologic halff-life Mo-99
alumina
column
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.
Lead shield
RADIONUCLIDE GENERATOR SYSTEMS
A number of radionuclides of interest in nuclear medicine • Fig. 1.4 Generator. Schematic of dry molybdenum-99/technetium-
are short-lived isotopes that emit only gamma rays and 99m generator system.
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 point, for instance, the amount of daughter is slightly
available from generators include technetium-99m, indium- greater than the activity of the parent (Fig. 1.5). When the
113m (113mIn), krypton-81m (81mKr), rubidium-82 (82Rb), parent isotope has a half-life somewhat greater than that of
strontium-87m (87mSr), and gallium-68 (68Ga). the daughter, the equilibrium attained is said to be a tran-
Inside the most common generator (99Mo-99mTc), a sient equilibrium. In the case of a 99Mo-99mTc generator,
radionuclide “parent” with a relatively long half-life is firmly because 12% of 99Mo decays directly to 99Tc without pro-
affixed to an ion exchange column. A 99Mo-99mTc generator ducing 99mTc, the activity of 99mTc in the generator only
consists of an alumina column on which 99Mo is bound. reaches 97% of the 99Mo activity.
The parent isotope (67-hour half-life) decays to its radioac- Most generators used in hospitals have 99Mo activity
tive daughter, 99mTc, which is a different element with a levels of about 1 to 19 Ci (3.7 to 70.3 GBq). The amount
shorter half-life (6 hours). Because the daughter is only of 99mTc in the generator reaches about half the theoretical
loosely bound on the column, it may be removed, or washed maximum in one half-life (6 hours). It reaches about three-
off, with an elution liquid such as normal (0.9%) saline. fourths of the theoretical maximum in about two half-lives,
Wet and dry 99Mo-99mTc generator systems are available and and so on (see Appendix C.1). This indicates that if one
differ only slightly. A wet system (most common in com- elutes all of the 99mTc daughter from a 99Mo generator, 24
mercial radiopharmacies) has a saline reservoir and a vacuum hours later (four half-lives), the amount of 99mTc present in
vial that draws saline across the column. With a dry system the generator will have returned to about 95% of the theo-
(most common in imaging clinics), a specific amount of retical maximum.
saline in a vial is placed on the generator entry port and Other, much less common photon-emitting radionu-
drawn across by a vacuum vial (Fig. 1.4). clide generator systems include rubidium-81 (81Rb) (4.5
After the daughter is separated from the column, the hours)/81mKr (13 seconds), tin-13 (113Sn) (115 days)/113mIn
buildup process is begun again by the residual parent (1.7 hours), yttrium-87 (87Y) (3.3 days)/87mSr (2.8 hours),
isotope. Uncommonly, some of the parent isotope (99Mo) and tellurium-132 (132Te) (3.2 days)/132I (2.3 hours).
or alumina is removed from the column during elution and Although generator systems are most often used to produce
appears in the eluate containing the daughter isotope. This photon-emitting radionuclides, certain generators can
is termed breakthrough. produce positron emitters. These include strontium-82
To make efficient use of a generator, elution times should (82Sr) (25 days)/82Rb (1.3 minutes). 82Rb is a potassium
be spaced appropriately to allow for reaccumulation of the analog and can be used for myocardial perfusion imaging
daughter isotope on the column. The short-lived daughter using positron emission tomography (PET). Gallium-68
reaches maximum activity when the rate of decay of the (68 minutes) is another positron emitter that can be pro-
daughter equals its rate of production. At this equilibrium duced from a germanium-68 (68Ge) (271 days) generator.

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6 C HA P T E R 1 Radioactivity, Radionuclides, and Radiopharmaceuticals

100
99mTc

separation 99mTc

transient
75 equilibrium

Activity %
50 99mTc

growth

99Mo decay
25

0
6 24 48 72
Hours
• Fig. 1.5 Radionuclide Buildup and Decay in a Generator. General schematic representation of
molybdenum-99 (99Mo) decay and technetium-99m (99mTc) buildup in a generator eluted at 0 hours
and again at 24 hours. See text regarding the reason that in reality the 99mTc activity never actually
exceeds 99Mo.

in Appendix E. Issues related to pediatric dose and preg-

RADIONUCLIDES AND RADIOPHARMA- nancy and breastfeeding are in Appendixes D and G.
CEUTICALS FOR IMAGING Although the localizing properties of radiopharmaceuti-
cals are generally sufficient to obtain adequate diagnostic
In evaluating the choice of a radionuclide to be used in the images, the localizing mechanisms may be altered by various
nuclear medicine laboratory, the following characteristics conditions in an individual patient, including the adminis-
are desirable: tration of other medications.
• Minimum of particulate emission
• Primary photon energy between 50 and 500 keV
• Physical half-life greater than the time required to prepare Single Photon
material for injection Technetium-99m
• Effective half-life longer than the examination time
• Suitable chemical form and reactivity Technetium-99m fulfills many of the criteria of an ideal
• Low toxicity radionuclide and is used in more than 80% of nuclear
• Stability or near-stability of the product imaging procedures in the United States. It has no partic-
The radionuclides most commonly used are shown in ulate emission, a 6-hour half-life, and a predominant
Tables 1.1 and 1.2. A radionuclide that has desirable (98%) 140-keV photon. The decay mode is 88% isomeric
imaging properties can usually be used to make a variety of transition and only a small amount (12%) of internal
radiopharmaceuticals. This is done by coupling the radio- conversion.
nuclide with various stable compounds that are localized by Technetium-99m is obtained by separating it from the
organs or disease states. Many radionuclides are radiophar- parent 99Mo (67-hour half-life) in a generator system.
maceuticals in their own right and can be administered Molybdenum-99 for generators is generally produced by
without alteration to obtain useful images. Commonly used neutron irradiation of 98Mo or by chemical separation of
235
imaging radiopharmaceuticals are shown in Table 1.3. The U fission products. In the latter case, 99Mo is nearly
biologic behavior of most of these radionuclides can be carrier free and has a high specific activity. In the alumina
markedly altered by a combination with additional sub- generator system, the molybdenum activity is absorbed on
stances to form other radiopharmaceuticals. an alumina column. By passing physiologic saline over the
Mechanisms of localization for some of these radio- column, 99mTc is eluted or washed off as sodium pertechne-
pharmaceuticals are listed in Table 1.4. The various tate (Na 99mTcO4–).
radiopharmaceuticals used in imaging procedures are addi- Technetium can exist in a variety of valence states,
tionally discussed in the appropriate chapters. Dosimetry ranging from −1 to +7. When eluted from an alumina
and protocols for the various radionuclides are presented column generator, 99mTc is present primarily as heptavalent

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 CHAPTER 1 Radioactivity, Radionuclides, and Radiopharmaceuticals 7

TABLE
1.1 Characteristics of Commonly Used Radionuclides

Symbol Physical Half-Life Approximate Energy

Photon-Emitting Radionuclides for Gamma (keV)
Imaging
99m
Technetium-99m Tc 6h 140
99
Molybdenum-99 Mo 67 h 181, 740, 780
123
Iodine-123 I 13.2 h 159
131
Iodine-131 I 8.0 days 364
133
Xenon-133 Xe 5.3 days 81
67
Gallium-67 Ga 78.3 h 93, 184, 296, 388
111
Indium-111 In 67 h 173, 247
113m
Indium-113m In 1.7 h 392
201
Thallium-201 Tl 73.1 h 69, 81 (x-rays from mercury daughter)
81m
Krypton-81m Kr 13 s 191
Positron-Emitting Radionuclides Positron (MeV) (Image 511-keV
for Imaging Photons)
11
Carbon-11 C 20.3 min 0.960
13
Nitrogen-13 N 10 min 1.198
15
Oxygen-15 O 124 s 1.730
18
Fluorine-18 F 110 min 0.634
68
Gallium-68 Ga 68 min 1.9
82
Rubidium-82 Rb 1.27 min 3.150
Unsealed Radionuclides Used for Emissions
Therapy
89
Strontium-89 Sr 50.5 days 1.46 MeV max; 0.58 MeV mean beta;
910 keV gamma (0.01%)
90
Yttrium-90 Y 64 h 2.2 MeV max; 0.93 MeV mean beta
131
Iodine-131 I 8.0 days 0.19 MeV mean beta; 364 keV gamma
(82%)
153
Samarium-153 Sm 46 h 0.81 MeV max; 0.23 MeV mean beta;
103 keV gamma (28%)
186
Rhenium-186 Re 90 h 0.34 MeV mean beta; 186 keV gamma (9%)
223
Radium-223 Ra 11.4 days 5–7.5 MeV alpha (94%);
beta 1 MeV (< 4%);
gamma (< 2%)

Note: The approximate range (cm) of a beta particle in tissue is the energy (MeV) divided by 2.

(+7) pertechnetate (TcO4–). In the preparation of radio- than half leaves the plasma within several minutes and is
pharmaceuticals, 99mTc pertechnetate can be reduced from distributed in the extracellular fluid. It rapidly concentrates
+7 to a lower valence state, usually +4, to permit the label- in the salivary glands, choroid plexus, thyroid gland, gastric
ing of various chelates. This is generally accomplished with mucosa, and functioning breast tissue; during pregnancy, it
stannous (tin) ions. crosses the placenta.
As pertechnetate, the technetium ion is a singly charged Excretion is by the gastrointestinal and renal routes.
anion and is similar in size to the iodide ion. After intrave- Although 99mTc pertechnetate is excreted by glomerular fil-
nous injection, 99mTc pertechnetate is loosely bound to tration, it is partially reabsorbed by the renal tubules; as a
protein and rapidly leaves the plasma compartment. More result, only 30% is eliminated in the urine during the first

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8 C HA P T E R 1 Radioactivity, Radionuclides, and Radiopharmaceuticals

TABLE
1.2 Characteristics of Common Positron Emission Tomography (PET) Radionuclides

Maximal and Maximum and

Nuclide (Decay Physical Average Positron Mean Range in
Product) Half-Life Decay Mode Energy (keV) Water (mm) Production Reaction
14
Carbon-11 20.3 min 99.8% positron 960, 385 4.1, 1.1 N(p,alpha)11C*
(Boron-11) 0.2% electron
capture
16
Nitrogen-13 10 min 100% positron 1198, 491 5.1, 1.4 O(p,alpha)13N; 13
C(p,n)13N
(Carbon-13)
15
Oxygen-15 124 s 99.9% positron 1730, 735 7.3, 1.5 N(p,n)15O; 14
N(d,n)15O
(Nitrogen-15)
18
Fluorine-18 110 min 97% positron 634, 250 2.4, 1.0 O(p,n)18F; 20Ne(d,alpha)18F;
16
(Oxygen-18) 3% electron capture O(3He,alpha)18F
68
Gallium-68 68 min 100% positron 1899 8.9, 2.9 Ge generator (T 12 271 days)
(Zinc-68)
82
Rubidium-82 75 s 96% positron 3150, 1385 14.1, 5.9 Sr generator (T 12 25.3 days)
(Krypton-82) 4% electron capture

*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.

Ant Ant of tissue between the radionuclide and the detector removes
about half of the photons of interest, and 4 inches removes
about three-fourths.

Iodine-123 and -131

Two isotopes of iodine (123I and 131I) are clinically useful for
imaging and may be administered as iodide. Iodine-123 has
a 13.2-hour half-life and decays by electron capture to
tellurium-123 (123Te). The photons emitted are 28-keV
(92%) and 159-keV (84%) gamma rays. Iodine-123 is
usually produced in a cyclotron by bombardment of
antimony-121 (121Sb) or tellurium-122 or -124 (122Te or
124
Te). Another method is to bombard iodine-127 (127I) to
produce 123Xe and let this decay to 123I. Contamination with
124
I may increase the radiation dose; because 124I is long
lived, its proportion in an 123I preparation increases
30 min 2h with time.
Iodine-131 is a much less satisfactory isotope from an
• Fig. 1.6 Whole-Body Distribution of Technetium-99m Sodium
Pertechnetate. Activity is seen in the salivary glands, thyroid gland,
imaging viewpoint because of the high radiation dose to the
saliva, stomach, and bladder. thyroid and its relatively high photon energy. However, it
is widely available, is relatively inexpensive, and has a rela-
tively long shelf life. Iodine-131 has a half-life of 8.06 days
and decays by beta-particle emission to a stable 131Xe. The
day. The ion is also secreted directly into the stomach and principal mean beta energy (90%) is 192 keV. Several
colon, with a much smaller amount coming from the small gamma rays are also emitted, and the predominant photon
bowel. The colon is the critical organ and receives about 1 is 364 keV (82% abundance) (HVL in water of 6.4 cm).
to 2 rad/10 mCi (0.04 mGy/MBq) of 99mTc pertechnetate When iodine is orally administered as the iodide ion, it
administered. The biodistribution of 99mTc pertechnetate is is readily absorbed from the gastrointestinal tract and dis-
shown in Fig. 1.6. The principal emission (140-keV photon) tributed in the extracellular fluid. It is concentrated in a
of 99mTc has a half-value layer (HVL) of 0.028 cm in lead manner similar to that for 99mTc pertechnetate in the sali-
and 4.5 cm in water. Because tissue is close to water in terms vary glands, thyroid, and gastric mucosa. As with pertech-
of attenuation characteristics, it is clear that about 2 inches netate, there is renal filtration with significant tubular

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 CHAPTER 1 Radioactivity, Radionuclides, and Radiopharmaceuticals 9

TABLE
1.3 Imaging Radiopharmaceuticals

Radionuclide Radiopharmaceutical Uses

Carbon-11 Acetate Prostate
Nitrogen-13 Ammonia Cardiac perfusion
Oxygen-15 Gas Brain perfusion
Water Metabolic agent
Fluorine-18 FDG (fluorodeoxyglucose) Tumor, cardiac viability, brain metabolism, infection
Sodium Bone
Florbetapir Amyloid
Gallium-67 Citrate Infection, tumor
Gallium-68 DOTATATE Neuroendocrine tumor
Krypton-81m Gas Pulmonary ventilation
Rubidium-82 Chloride Myocardial perfusion
Technetium-99m Diphosphonate Bone
DISIDA (diisopropyl iminodiacetic acid) Biliary
DMSA (dimercaptosuccinic acid) Renal cortical
DTPA (diethylenetriamine pentaacetic acid) Renal dynamic, brain, lung ventilation
ECD (ethyl cysteinate dimmer) Brain perfusion
Glucoheptonate Brain, renal dynamic
HMPAO (hexamethylpropyleneamine oxine) Brain perfusion
HMPAO labeled white cells Infection
Labeled red cells Gastrointestinal (GI) blood loss, cardiac function,
hepatic hemangioma
MAA (macroaggregated albumin) Lung perfusion, LeVeen shunt patency, intraarterial
liver
MAG3 (mercaptoacetyltriglycine) Renal
Mebrofenin Biliary
Pertechnetate Thyroid, salivary glands, Meckel diverticulum,
testicular
Sestamibi Myocardial perfusion, parathyroid, breast
Sulfur colloid Liver/spleen, red bone marrow, esophageal transit,
gastric emptying
Sulfur colloid (filtered) Lymphoscintigraphy
Tetrofosmin Myocardial perfusion
Indium-111 DTPA Cerebrospinal fluid (CSF) flow, gastric liquid
emptying
Oxine labeled white cells Infection
Pentetreotide Somatostatin receptor tumors
Iodine-123 Sodium Thyroid
MIBI (metaiodobenzylguanidine) Pheochromocytoma, adrenal medullary, neural
crest tumors
Iodine-131 Sodium Thyroid cancer
Xenon-133 Gas Lung ventilation
Thallium-201 Chloride Myocardial perfusion

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10 C HA P T E R 1 Radioactivity, Radionuclides, and Radiopharmaceuticals

TABLE
1.4 Mechanisms of Localization and Examples

Capillary blockade Macroaggregated albumin in lung

Diffusion Filtration of DTPA by kidney
Sequestration Leukocytes for abscess scanning
Labeled platelets (damaged endothelium)
Heat-damaged red blood cells for splenic scanning
Phagocytosis Colloid scanning for liver and spleen, bone marrow, and lymph nodes
Receptor binding Neuroreceptor imaging
Active transport Iodocholesterol in adrenal scanning
Iodine or pertechnetate (accumulation by choroid plexus, Meckel diverticulum, salivary gland,
stomach, and thyroid)
Technetium-99m IDA analogs in liver/biliary tract
Orthoiodohippurate in renal tubules
Thallous ions in myocardium
Metabolism Fluorodeoxyglucose imaging of brain, tumor, and myocardium
Compartmental containment Labeled red blood cells for gated blood pool studies
Compartmental leakage Labeled red blood cells for detection of gastrointestinal bleeding
Physicochemical adsorption Phosphate bone-scanning agents
Antibody–antigen reactions Tumor imaging, monoclonal antibodies

DTPA, Diethylenetriaminepentaacetic acid; IDA, iminodiacetic acid.

reabsorption. Urinary excretion is the predominant route produced by a variety of reactions in a cyclotron. The prin-
(35% to 75% in 24 hours), although there is some fecal cipal gamma photons from 67Ga are 93 keV (40%), 184 keV
excretion as well. Iodine-131 trapped and organified by the (24%), 296 keV (22%), and 388 keV (7%). An easy way
normal thyroid has an effective half-life of about 7 days. to remember these energies is to round off the figures (i.e.,
Iodine is a useful radionuclide because it is chemically reac- 90, 190, 290, and 390 keV).
tive and is used to produce a variety of radiopharmaceuti- When injected intravenously, most 67Ga is immediately
cals, which are discussed in later clinical chapters. bound to plasma proteins, primarily transferrin. During
the first 12 to 24 hours, excretion from the body is pri-
Xenon-133 marily through the kidneys, with 20% to 25% of the
administered dose being excreted by 24 hours. After that
Xenon is a relatively insoluble inert gas and is most com- time, the intestinal mucosa becomes the major route of
monly used for pulmonary ventilation studies. Xenon is elimination. Typically on images, activity is seen in the
commercially available in unit-dose vials or in 1 Ci (37 GBq) liver and to a lesser extent the spleen. In addition to activ-
glass ampules. Xenon is highly soluble in oil and fat, and ity within the axial skeleton, liver, spleen, and bowel, con-
there is some adsorption of xenon onto plastic syringes. centration is also seen in the salivary and lacrimal glands,
Xenon-133 has a physical half-life of 5.3 days. The prin- as well as in the breasts and external genitalia. If imaging
cipal gamma photon has an energy of 81 keV and emits a is performed in the first 24 hours, kidney and bladder
374-keV beta particle. With normal pulmonary function, activity may also be noted.
its biologic half-life is about 30 seconds. Some disadvan-
tages of 133Xe include its relatively low photon energy, beta- Indium-111
particle emission, and some solubility in both blood
and fat. Indium is a metal that can be used as an iron analog; it is
similar to gallium. Isotopes of interest are 111In and 113mIn.
Gallium-67 Indium-111 has a physical half-life of 67 hours and is pro-
duced by a cyclotron. The principal photons are 173 keV
Gallium-67 has a physical half-life of 78.3 hours and decays (89%) and 247 keV (94%). Indium-113m can be conve-
by electron capture, emitting gamma radiation. It can be niently produced by using a 113Sn generator system. It has

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 CHAPTER 1 Radioactivity, Radionuclides, and Radiopharmaceuticals 11

a physical half-life of 1.7 hours and a photon of about

392 keV. Indium-111 can be prepared as a chelate with Positron Emitters
diethylenetriaminepentaacetic acid (DTPA). Because of its Fluorine-18
long half-life, the 111In chelate can be used for intracranial
cisternography. Indium-111 is also used to label platelets, The most commonly used positron-emitting radiopharma-
white cells, monoclonal antibodies, and peptides. Indium- ceutical in clinical imaging is the glucose analog fluorine-18
111 oxine labeled white cells are commonly used to scan fluorodeoxyglucose (18F-FDG). Many tumor cells use large
for infections. On these images, activity is seen mostly in amounts of glucose as an energy source and possess increased
the spleen and to a lesser extent in the liver and bone expression of glucose transporters (especially GLUT1) and
marrow (see Chapter 12). increased hexokinase activity (especially HK2). Glucose
transporters transfer glucose and fluorodeoxyglucose into
Thallium-201 the cells, where they are phosphorylated by hexokinases (Fig.
1.7). The rate-limiting step in this process is at the hexoki-
When a thallium metal target is bombarded with protons nase level and not at glucose transport. Although phosphor-
in a cyclotron, lead 201 (201Pb) is produced, which can be ylated glucose can be further metabolized, phosphorylated
separated from the thallium target and allowed to decay to FDG cannot be rapidly metabolized and 18F-FDG is essen-
201
Tl. Thallium-201 has a physical half-life of 73.1 hours tially trapped within the cell in proportion to the rate of
and decays by electron capture to mercury-201 (201Hg). glucose metabolism. This allows sufficient time to image
Mercury-201 emits characteristic x-rays with energies from its distribution in normal and abnormal bodily tissues. A
68 to 80 keV (94.5%) and much smaller amounts of notable exception to the trapping of phosphorylated FDG
gamma rays with higher energies. The relatively low energy is the liver, in which an abundance of phosphatases causes
of the major emissions can cause significant attenuation by enhanced dephosphorylation of FDG-6-phosphate, which
tissue between the radionuclide and the gamma camera. accelerates its washout from that organ.
The HVL in water is about 4 cm. For these reasons, attenu- Although 18F-FDG reaches a plateau of accumulation in
ation correction methodologies have been developed (see tumors at about 45 minutes after injection, the tumor-to-
Chapter 2). Because 201Tl is produced by a cyclotron, it is background ratio is best at 2 to 3 hours. Highest activity
expensive. Thallium-201 is normally administered as a chlo- levels at 2 hours are seen in the brain, heart (if not fasting),
ride and rapidly clears from the blood with a half-life and urinary system.
between 30 seconds and 3 minutes. Because it is roughly The effective dose to the patient for most 18F-FDG PET
a potassium analog, it is rapidly distributed throughout scans is about 0.1 rem (1 mSv) or about 0.093 rem/mCi
the body, particularly in skeletal and cardiac muscle. (0.025 mSv/MBq). Pregnancy and breastfeeding are
Thallium-202 (95% photon at 439 keV) contamination common concerns when administering radionuclides to
should be less than 0.5% and, if present in greater quanti- women. Fetal dose estimates after administration of
ties, can significantly degrade images. 13.5 mCi (500 MBq) of 18F-FDG to the mother are about

Cell membrane Intracellular

Glucose Glucose
Phosphorylation

Glucose 6-p

Glucose

Glucose
18
F-FDG transporter 18
F-FDG
(GLUT) Phosphorylation
18
F-FDG 6-p
Blocked

• Fig. 1.7 18
F-FDG Metabolism. Although 18F-FDG is transported into the cell in the same manner as
glucose, it cannot be dephosphorylated and remains in the cell. FDG, Fluorodeoxyglucose.

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