1

chapter
What Is Nuclear
Medicine?
A. FUNDAMENTAL CONCEPTS
The science and clinical practice of nuclear
medicine involve the administration of trace
amounts of compounds labeled with radioac-
tivity (radionuclides) that are used to provide
diagnostic information in a wide range of
disease states. Although radionuclides also
have some therapeutic uses, with similar
underlying physics principles, this book
focuses on the diagnostic uses of radionu-
clides in modern medicine.
In its most basic form, a nuclear medicine
study involves injecting a compound, which
is labeled with a gamma-ray-emitting or
positron-emitting radionuclide, into the body.
The radiolabeled compound is called a radio-
pharmaceutical, or more commonly, a tracer
or radiotracer. When the radionuclide decays,
gamma rays or high-energy photons are
emitted. The energy of these gamma rays or
photons is such that a signicant number can
exit the body without being scattered or
attenuated. An external, position-sensitive
gamma-ray camera can detect the gamma
rays or photons and form an image of the
distribution of the radionuclide, and hence
the compound (including radiolabeled prod-
ucts of reactions of that compound) to which
it was attached.
There are two broad classes of nuclear
medicine imaging: single photon imaging
[which includes single photon emission com-
puted tomography (SPECT)] and positron
imaging [positron emission tomography
(PET)]. Single photon imaging uses radionu-
clides that decay by gamma-ray emission. A
planar image is obtained by taking a picture
of the radionuclide distribution in the patient
from one particular angle. This results in an
image with little depth information, but which
can still be diagnostically useful (e.g., in bone
scans, where there is not much tracer uptake
in the tissue lying above and below the bones).
For the tomographic mode of single photon
imaging (SPECT), data are collected from
many angles around the patient. This allows
cross-sectional images of the distribution of
the radionuclide to be reconstructed, thus
providing the depth information missing from
planar imaging.
Positron imaging makes use of radio-
nuclides that decay by positron emission. The
emitted positron has a very short lifetime
and, following annihilation with an electron,
simultaneously produces two high-energy
photons that subsequently are detected by an
imaging camera. Once again, tomographic
images are formed by collecting data from
many angles around the patient, resulting in
PET images.
B. THE POWER OF NUCLEAR
MEDICINE
The power of nuclear medicine lies in its
ability to provide exquisitely sensitive mea-
sures of a wide range of biologic processes in
the body. Other medical imaging modalities
such as magnetic resonance imaging (MRI),
x-ray imaging, and x-ray computed tomog-
raphy (CT) provide outstanding anatomic
images but are limited in their ability to
provide biologic information. For example,
magnetic resonance methods generally have
a lower limit of detection in the millimolar
concentration range ( 6 10
17
molecules per
mL tissue), whereas nuclear medicine studies
routinely detect radio labeled substances in
the nanomolar ( 6 10
11
molecules per mL
tissue) or picomolar ( 6 10
8
molecules
per mL tissue) range. This sensitivity advan-
tage, together with the ever-growing selection
1
2 Physics in Nuclear Medicine
inside the human body noninvasively for the
rst time and was particularly useful for
the imaging of bone. X rays soon became the
method of choice for producing radiographs
because images could be obtained more quickly
and with better contrast than those provided
by radium or other naturally occurring radio-
nuclides that were available at that time.
Although the eld of diagnostic x-ray imaging
rapidly gained acceptance, nuclear medicine
had to await further developments.
The biologic foundations for nuclear medi-
cine were laid down between 1910 and 1945.
In 1913, Georg de Hevesy developed the prin-
ciples of the tracer approach
2
and was the
rst to apply them to a biologic system in
1923, studying the absorption and transloca-
tion of radioactive lead nitrate in plants.
3

The rst human study employing radioactive
tracers was probably that of Blumgart and
Weiss (1927),
4
who injected an aqueous solu-
tion of radon intravenously and measured the
transit time of the blood from one arm to the
other using a cloud chamber as the radiation
detector. In the 1930s, with the invention of
the cyclotron by Lawrence (Fig. 1-1),
5
it
became possible to articially produce new
radionuclides, thereby extending the range of
biologic processes that could be studied. Once
again, de Hevesy was at the forefront of using
these new radionuclides to study biologic pro-
cesses in plants and in red blood cells. Finally,
at the end of the Second World War, the
nuclear reactor facilities that were developed
as part of the Manhattan Project started to
be used for the production of radioactive
isotopes in quantities sufcient for medical
applications.
The 1950s saw the development of technol-
ogy that allowed one to obtain images of the
distribution of radionuclides in the human
body rather than just counting at a few mea-
surement points. Major milestones included
the development of the rectilinear scanner in
1951 by Benedict Cassen
6
(Fig. 1-2) and the
Anger camera, the forerunner of all modern
nuclear medicine single-photon imaging
systems, developed in 1958 by Hal Anger (Fig.
1-3).
7
In 1951, the use of positron emitters
and the advantageous imaging properties of
these radionuclides also were described by
Wrenn and coworkers.
8
Until the early 1960s, the edgling eld of
nuclear medicine primarily used
131
I in the
study and diagnosis of thyroid disorders and
an assortment of other radionuclides that
were individually suitable for only a few spe-
cic organs. The use of
99m
Tc for imaging in
of radiolabeled compounds, allows nuclear
medicine studies to be targeted to the very
specic biologic processes underlying disease.
Examples of the diverse biologic processes
that can be measured by nuclear medicine
techniques include tissue perfusion, glucose
metabolism, the somatostatin receptor status
of tumors, the density of dopamine receptors
in the brain, and gene expression.
Because radiation detectors can easily
detect very tiny amounts of radioactivity, and
because radiochemists are able to label com-
pounds with very high specic activity (a
large fraction of the injected molecules are
labeled with a radioactive atom), it is possible
to form high-quality images even with nano-
molar or picomolar concentrations of com-
pounds. Thus trace amounts of a compound,
typically many orders of magnitude below the
millimolar to micromolar concentrations that
generally are required for pharmacologic
effects, can be injected and followed safely
over time without perturbing the biologic
system. Like CT, there is a small radiation
dose associated with performing nuclear med-
icine studies, with specic doses to the differ-
ent organs depending on the radionuclide, as
well as the spatial and temporal distribution
of the particular radiolabeled compound that
is being studied. The safe dose for human
studies is established through careful dosim-
etry for every new radiopharmaceutical that
is approved for human use.
C. HISTORICAL OVERVIEW
As with the development of any eld of science
or medicine, the history of nuclear medicine
is a complex topic, involving contributions
from a large number of scientists, engineers,
and physicians. A complete overview is well
beyond the scope of this book; however, a few
highlights serve to place the development of
nuclear medicine in its appropriate historical
context.
The origins of nuclear medicine
1
can be
traced back to the last years of the 19th
century and the discovery of radioactivity by
Henri Becquerel (1896) and of radium by
Marie Curie (1898). These developments came
close on the heels of the discovery of x rays in
1895 by Wilhelm Roentgen. Both x rays and
radium sources were quickly adopted for
medical applications and were used to make
shadow images in which the radiation was
transmitted through the body and onto photo-
graphic plates. This allowed physicians to see
1 What Is Nuclear Medicine? 3
FIGURE 1-1 Ernest O. Lawrence
standing next to the cyclotron he
invented at Berkeley, California.
(From Myers WG, Wagner HN:
Nuclear medicine: How it began.
Hosp Pract 9:103-113, 1974.)
FIGURE 1-2 Left, Benedict Cassen with his rectilinear scanner (1951), a simple scintillation counter (see Chapter 7)
that scans back and forth across the patient. Right, Thyroid scans from an early rectilinear scanner following admin-
istration of
131
I. The output of the scintillation counter controlled the movement of an ink pen to produce the rst
nuclear medicine images. (Left, Courtesy William H. Blahd, MD; with permission of Radiology Centennial, Inc. Right,
From Cassen B, Curtis L, Reed C, Libby R: Instrumentation for
131
I use in medical studies. Nucleonics 9:46-50, 1951.)
4 Physics in Nuclear Medicine
FIGURE 1-3 Left, Hal Anger with the rst gamma camera in 1958. Right,
99m
Tc-pertechnetate brain scan of a patient
with glioma at Vanderbilt University Hospital (1971). Each image represents a different view of the head. The glioma
is indicated by an arrow in one of the views. In the 1960s, this was the only noninvasive test that could provide images
showing pathologic conditions inside the human brain. These studies played a major role in establishing nuclear medi-
cine as an integral part of the diagnostic services in hospitals. (Left, From Myers WG: The Anger scintillation camera
becomes of age. J Nucl Med 20:565-567, 1979. Right, Courtesy Dennis D. Patton, MD, University of Arizona, Tucson,
Arizona.)
1964 by Paul Harper and colleagues
9
changed
this and was a major turning point for the
development of nuclear medicine. The gamma
rays emitted by
99m
Tc had very good proper-
ties for imaging. It also proved to be very
exible for labeling a wide variety of com-
pounds that could be used to study virtually
every organ in the body. Equally important,
it could be produced in a relatively long-lived
generator form, allowing hospitals to have a
readily available supply of the radionuclide.
Today,
99m
Tc is the most widely used radionu-
clide in nuclear medicine.
The nal important development was
the mathematics to reconstruct tomographic
images from a set of angular views around
the patient. This revolutionized the whole
eld of medical imaging (leading to CT,
PET, SPECT and MRI) because it replaced
the two-dimensional representation of the
three-dimensional radioactivity distribution,
with a true three-dimensional representa-
tion. This allowed the development of PET
by Phelps and colleagues
10
and SPECT by
Kuhl and colleagues
11
during the 1970s and
marked the start of the modern era of
nuclear medicine.
D. CURRENT PRACTICE OF NUCLEAR
MEDICINE
Nuclear medicine is used for a wide variety of
diagnostic tests. There were roughly 100 dif-
ferent diagnostic imaging procedures avail-
able in 2006.
*
These procedures use many
different radiolabeled compounds, cover all
the major organ systems in the body, and
provide many different measures of biologic
function. Table 1-1 lists some of the more
common clinical procedures.
As of 2008, more than 30 million nuclear
medicine imaging procedures were performed
on a global basis.

There are more than 20,000

nuclear medicine cameras capable of imaging
gamma-ray-emitting radionuclides installed
in hospitals across the world. Even many
small hospitals have their own nuclear medi-
cine clinic. There also were more than 3,000
PET scanners installed in the world perform-
ing on the order of 4 million procedures
*Data courtesy Society of Nuclear Medicine, Reston,
Virginia.

Data courtesy Siemens Molecular Imaging, Hoffman

Estates, Illinois.
1 What Is Nuclear Medicine? 5
annually. The short half-lives of the most
commonly used positron-emitting radionu-
clides require an onsite accelerator or deliv-
ery of PET radiopharmaceuticals from
regional radiopharmacies. To meet this need,
there is now a PET radiopharmacy within 100
miles of approximately 90% of the hospital
beds in the United States. The growth of
clinical PET has been driven by the utility
of a metabolic tracer,
18
F-uorodeoxyglucose,
which has widespread applications in cancer,
heart disease, and neurologic disorders.
One major paradigm shift that has occurred
since the turn of the millennium has been
toward multimodality instrumentation. Vir-
tually all PET scanners, and a rapidly growing
number of SPECT systems, are now inte-
grated with a CT scanner in combined PET/
CT and SPECT/CT congurations. These
systems enable the facile correlation of struc-
ture (CT) and function (PET or SPECT),
yielding better diagnostic insight in many
clinical situations. The combination of nuclear
medicine scanners with MRI systems also is
under inve s tigation, and as of 2011, rst
commercial PET/MRI systems were being
delivered.
In addition to its clinical role, PET (and to
a certain extent, SPECT) continues to play a
major role in the biomedical research com-
munity. PET has become an established and
powerful research tool for quantitatively and
noninvasively measuring the rates of biologic
processes, both in the healthy and diseased
state. In this research environment, the
radiolabeled compounds and clinical nuclear
medicine assays of the future are being devel-
oped. In preclinical, translational and clinical
research, nuclear medicine has been at the
forefront in developing new diagnostic oppor-
tunities in the eld of molecular medicine,
created by the merger of biology and medi-
cine. A rapid growth is now occurring in the
number and diversity of PET and SPECT
molecular imaging tracers targeted to specic
proteins and molecular pathways implicated
in disease. These nuclear medicine technolo-
gies also have been embraced by the pharma-
ceutical and biotechnology industries to aid in
drug development and validation.
TABLE 1-1
SELECTED CLINICAL NUCLEAR MEDICINE PROCEDURES
Radiopharmaceutical Imaging Measurement Examples of Clinical Use
99m
Tc-MDP Planar Bone metabolism Metastatic spread of cancer,
osteomyelitis vs. cellulitis
99m
Tc-sestamibi (Cardiolite) SPECT or
planar
Myocardial perfusion Coronary artery disease
99m
Tc-tetrofosmin (Myoview)
201
Tl-thallous chloride
99m
Tc-MAG3 Planar Renal function Kidney disease
99m
Tc-DTPA
99m
Tc-HMPAO (Ceretec) SPECT Cerebral blood ow Neurologic disorders
99m
Tc-ECD SPECT Cerebral blood ow Neurologic disorders
123
I-sodium iodide Planar Thyroid function Thyroid disorders
131
I-sodium iodide Thyroid cancer
67
Ga-gallium citrate Planar Sequestered in tumors Tumor localization
99m
Tc-macroaggregated
albumin and
133
Xe gas
Planar Lung perfusion/
ventilation
Pulmonary embolism
111
In-labeled white blood
cells
Planar Sites of infection Detection of inammation
18
F-uorodeoxyglucose PET Glucose metabolism Cancer, neurological
disorders, and myocardial
diseases
82
Rb-rubidium chloride PET Myocardial perfusion Coronary artery disease
MDP, methylene diphosphonate; MAG3, mercapto-acetyl-triglycine; DTPA, diethylenetriaminepenta-acetic acid;
HMPAO, hexamethylpropyleneamine oxime; ECD, ethyl-cysteine-dimer; SPECT, single photon emission computed
tomography; PET, positron emission tomography.
6 Physics in Nuclear Medicine
5. Lawrence EO, Livingston MS: The production of
high-speed light ions without the use of high volt-
ages. Phys Rev 40:19-30, 1932.
6. Cassen B, Curtis L, Reed C, Libby R: Instrumenta-
tion for
131
I use in medical studies. Nucleonics 9:46-
50, 1951.
7. Anger HO: Scintillation camera. Rev Sci Instr 29:27-
33, 1958.
8. Wrenn FR, Good ML, Handler P: The use of positron-
emitting radioisotopes for the localization of brain
tumors. Science 113:525-527, 1951.
9. Harper PV, Beck R, Charleston D, Lathrop KA: Opti-
mization of a scanning method using technetium-
99m. Nucleonics 22:50-54, 1964.
10. Phelps ME, Hoffman EJ, Mullani NA, Ter Pogossian
MM: Application of annihilation coincidence detec-
tion of transaxial reconstruction tomography. J Nucl
Med 16:210-215, 1975.
11. Kuhl DE, Edwards RQ, Ricci AR, et al: The Mark IV
system for radionuclide computed tomography of the
brain. Radiology 121:405-413, 1976.
BIBLIOGRAPHY
For further details on the history of nuclear
medicine, we recommend the following:
Myers WG, Wagner HN: Nuclear medicine: How it began.
Hosp Pract 9(3):103-113, 1974.
Nutt R: The history of positron emission tomography. Mol
Imaging Biol 4:11-26, 2002.
Thomas AMK, editor: The Invisible Light: One Hundred
Years of Medical Radiology, Oxford, England, 1995,
Blackwell Scientic.
Webb S: From the Watching of Shadows: The Origins of
Radiological Tomography, Bristol, England, 1990,
Adam Hilger.
Recommended texts that cover clinical nuclear
medicine in detail are the following:
Ell P, Gambhir S, editors: Nuclear Medicine in Clinical
Diagnosis and Treatment, ed 3, Edinburgh, Scotland,
2004, Churchill Livingstone.
Sandler MP, Coleman RE, Patton JA, et al, editors: Diag-
nostic Nuclear Medicine, ed 4, Baltimore, 2002, Wil-
liams & Wilkins.
Schiepers C, editor: Diagnostic Nuclear Medicine, ed 2,
New York, 2006, Springer.
Von Schulthess GK, editor: Molecular Anatomic Imaging:
PET-CT and SPECT-CT Integrated Modality Imaging,
ed 2, Philadelphia, 2006, Lippincott, Williams and
Wilkins.
E. THE ROLE OF PHYSICS IN NUCLEAR
MEDICINE
Although the physics underlying nuclear
medicine is not changing, the technology for
producing radioactive tracers and for obtain-
ing images of those tracer distributions most
certainly is. We can expect to continue seeing
major improvements in nuclear medicine
technology, which will come from combining
advances in detector and accelerator physics,
electronics, signal processing, and computer
technology with the underlying physics of
nuclear medicine. Methods for accurately
quantifying the concentrations of radio labeled
tracers in structures of interest, measuring
biologic processes, and then relaying this
information to the physician in a clinically
meaningful and biologically relevant format
are also an important challenge for the future.
Renement in the models used in dosimetry
will allow better characterization of radiation
exposure and make nuclear medicine even
safer than it already is. Physics therefore con-
tinues to play an important and continuing
role in providing high-quality, cost-effective,
quantitative, reliable, and safe biologic assays
in living humans.
REFERENCES
1. Mould RF: A Century of X-Rays and Radioactivity in
Medicine, Bristol, 1993, Institute of Physics.
2. de Hevesy G: Radioelements as tracers in physics and
chemistry. Chem News 108:166, 1913.
3. de Hevesy G: The absorption and translocation of
lead by plants: A contribution to the application of
the method of radioactive indicators in the investiga-
tion of the change of substance in plants. Biochem J
17:439-445, 1923.
4. Blumgart HL, Weiss S: Studies on the velocity of
blood ow. J Clin Invest 4:15-31, 1927.