Nuclear Medicine

Nuclear medicine is defined as the branch of medicine that uses radioactive isotopes,

nuclear radiation, electromagnetic variations of the components of the atomic nucleus and related
biophysical techniques for the prevention, diagnosis, therapy and medical research.
Clinical applications of radiopharmaceuticals cover virtually all medical specialties.

Nuclear medicine is closely related to several basic and applied sciences such as physics,
chemistry, electronics, cybernetics and pharmacy, and other branches of medicine and
physiology, pathophysiology, radiology and other diagnostic techniques for the image.

At present, most of the hospitals and health centers have a Department of Radiology and a
Department of nuclear medicine, and radiochemical laboratory methods used for diagnosis and
research of a variety of diseases.

Definition of the specialty and scope of nuclear

medicine
 
Nuclear medicine is a medical specialty that uses radioactive isotopes, nuclear radiation,
electromagnetic variations of the components of the atomic nucleus and related to the prevention,
diagnosis, therapy and medical research biophysical techniques. Also, nuclear medicine includes
the study of biological phenomena resulting from the use of radioisotopes, as well as the use of
cyclotrons and nuclear reactors in the production of radionuclides for medical use, and applying
image reconstruction systems and data processing.
Its scope includes the following:

● Prevention: In this regard, the nuclear medicine applies the knowledge and skills that are
proper hygiene, prophylactic and preventive medicine and radiation protection.
● Research: Nuclear medicine is developed in basic and applied research
using radioactive isotopes and related biophysical techniques.
● Diagnosis: mainly includes the realization of functional, morphological, dynamic
morphological and functional and analytical tests based on biochemical, physiological and
pathophysiological principles, aimed at achieving a better knowledge and understanding of
the structure and function of the human body in health or disease.
● Therapeutics: In addition to the important impact of diagnostic techniques of nuclear
medicine for the treatment and management of patients, this specialty includes in its scope,
some specific therapeutic indications made by the administration of radiopharmaceuticals to
patients (therapy metabolic, endolymphatic, intracavitary, etc.). It also includes the treatment
and prevention of biological effects from exposure to ionizing radiation, especially when
exposure is due to external radiation or radioactive substances caused by pollution unsealed.
Nuclear medicine is a medical specialty involving the application of radioactive substances in the
diagnosis and treatment of disease. Nuclear medicine, in a sense, is "radiology done inside out" or
"endoradiology" because it records radiation emitting from within the body rather than radiation that
is generated by external sources like X-rays. In addition, nuclear medicine scans differ from
radiology as the emphasis is not on imaging anatomy but the function and for such reason, it is
called a physiological imaging modality. Single photon emission computed tomography (SPECT)
and positron emission tomography (PET) scans are the two most common imaging modalities in
nuclear medicine.

Diagnostic medical imaging[edit]

Diagnostic[edit]
In nuclear medicine imaging, radiopharmaceuticals are taken internally, for example, intravenously
or orally. Then, external detectors (gamma cameras) capture and form images from the radiation
emitted by the radiopharmaceuticals. This process is unlike a diagnostic X-ray, where external
radiation is passed through the body to form an image.
There are several techniques of diagnostic nuclear medicine.

● 2D: Scintigraphy ("scint") is the use of internal radionuclides to create two-dimensional images.[2]

●
A nuclear medicine whole body bone scan. The nuclear medicine whole body bone scan is generally
used in evaluations of various bone-related pathology, such as for bone pain, stress fracture,
nonmalignant bone lesions, bone infections, or the spread of cancer to the bone.
 

●
Nuclear medicine myocardial perfusion scan with thallium-201 for the rest images (bottom rows) and Tc-
Sestamibi for the stress images (top rows). The nuclear medicine myocardial perfusion scan plays a
pivotal role in the noninvasive evaluation of coronary artery disease. The study not only identifies
patients with coronary artery disease; it also provides overall prognostic information or overall risk of
adverse cardiac events for the patient.
 
 ●
A nuclear medicine parathyroid scan demonstrates a parathyroid adenoma adjacent to the left inferior
pole of the thyroid gland. The above study was performed with Technetium-Sestamibi (1st column) and
iodine-123 (2nd column) simultaneous imaging and the subtraction technique (3rd column).
 

●
Normal hepatobiliary scan (HIDA scan). The nuclear medicine hepatobiliary scan is clinically useful in the
detection of the gallbladder disease.
 

●
Normal pulmonary ventilation and perfusion (V/Q) scan. The nuclear medicine V/Q scan is useful in the
evaluation of pulmonary embolism.
 

●
Thyroid scan with iodine-123 for evaluation of hyperthyroidism.

● 3D: SPECT is a 3D tomographic technique that uses gamma camera data from many
projections and can be reconstructed in different planes. Positron emission tomography (PET)
uses coincidence detection to image functional processes.
 ●
A nuclear medicine SPECT liver scan with technetium-99m labeled autologous red blood cells. A focus
of high uptake (arrow) in the liver is consistent with a hemangioma.
 

●
Maximum intensity projection (MIP) of a whole-body positron emission tomography (PET) acquisition of a
79 kg female after intravenous injection of 371 MBq of 18F-FDG (one hour prior measurement).
Nuclear medicine tests differ from most other imaging modalities in that diagnostic tests primarily
show the physiological function of the system being investigated as opposed to traditional
anatomical imaging such as CT or MRI. Nuclear medicine imaging studies are generally more
organ-, tissue- or disease-specific (e.g.: lungs scan, heart scan, bone scan, brain scan, tumor,
infection, Parkinson etc.) than those in conventional radiology imaging, which focus on a particular
section of the body (e.g.: chest X-ray, abdomen/pelvis CT scan, head CT scan, etc.). In addition,
there are nuclear medicine studies that allow imaging of the whole body based on certain cellular
receptors or functions. Examples are whole body PET scans or PET/CT scans, gallium
scans, indium white blood cell scans, MIBG and octreotide scans.

Iodine-123 whole body scan for thyroid cancer evaluation. The study above was performed after the total
thyroidectomy and TSH stimulation with thyroid hormone medication withdrawal. The study shows a small
residual thyroid tissue in the neck and a mediastinum lesion, consistent with the thyroid cancer metastatic
disease. The observable uptakes in the stomach and bladder are normal physiologic findings.

While the ability of nuclear metabolism to image disease processes from differences in metabolism
is unsurpassed, it is not unique. Certain techniques such as fMRI image tissues (particularly cerebral
tissues) by blood flow and thus show metabolism. Also, contrast-enhancement techniques in both
CT and MRI show regions of tissue that are handling pharmaceuticals differently, due to an
inflammatory process.
Diagnostic tests in nuclear medicine exploit the way that the body handles substances differently
when there is disease or pathology present. The radionuclide introduced into the body is often
chemically bound to a complex that acts characteristically within the body; this is commonly known
as a tracer. In the presence of disease, a tracer will often be distributed around the body and/or
processed differently. For example, the ligand methylene-diphosphonate (MDP) can be preferentially
taken up by bone. By chemically attaching technetium-99m to MDP, radioactivity can be transported
and attached to bone via the hydroxyapatite for imaging. Any increased physiological function, such
as due to a fracture in the bone, will usually mean increased concentration of the tracer. This often
results in the appearance of a "hot spot", which is a focal increase in radio accumulation or a general
increase in radio accumulation throughout the physiological system. Some disease processes result
in the exclusion of a tracer, resulting in the appearance of a "cold spot". Many tracer complexes
have been developed to image or treat many different organs, glands, and physiological processes.

Hybrid scanning techniques[edit]

In some centers, the nuclear medicine scans can be superimposed, using software or hybrid
cameras, on images from modalities such as CT or MRI to highlight the part of the body in which the
radiopharmaceutical is concentrated. This practice is often referred to as image fusion or co-
registration, for example SPECT/CT and PET/CT. The fusion imaging technique in nuclear medicine
provides information about the anatomy and function, which would otherwise be unavailable or
would require a more invasive procedure or surgery.

●
Normal whole body PET/CT scan with FDG-18. The whole body PET/CT scan is commonly used in the
detection, staging and follow-up of various cancers.
 

●
Abnormal whole body PET/CT scan with multiple metastases from a cancer. The whole body PET/CT
scan has become an important tool in the evaluation of cancer.

Practical concerns in nuclear imaging[edit]

Although the risks of low-level radiation exposures are not well understood, a cautious approach has
been universally adopted that all human radiation exposures should be kept As Low As Reasonably
Practicable, "ALARP". (Originally, this was known as "As Low As Reasonably Achievable" (ALARA),
but this has changed in modern draftings of the legislation to add more emphasis on the
"Reasonably" and less on the "Achievable".)
Working with the ALARP principle, before a patient is exposed for a nuclear medicine examination,
the benefit of the examination must be identified. This needs to take into account the particular
circumstances of the patient in question, where appropriate. For instance, if a patient is unlikely to be
able to tolerate a sufficient amount of the procedure to achieve a diagnosis, then it would be
inappropriate to proceed with injecting the patient with the radioactive tracer.
When the benefit does justify the procedure, then the radiation exposure (the amount of radiation
given to the patient) should also be kept as low as reasonably practicable. This means that the
images produced in nuclear medicine should never be better than required for confident diagnosis.
Giving larger radiation exposures can reduce the noise in an image and make it more
photographically appealing, but if the clinical question can be answered without this level of detail,
then this is inappropriate.
As a result, the radiation dose from nuclear medicine imaging varies greatly depending on the type
of study. The effective radiation dose can be lower than or comparable to or can far exceed the
general day-to-day environmental annual background radiation dose. Likewise, it can also be less
than, in the range of, or higher than the radiation dose from an abdomen/pelvis CT scan.
Some nuclear medicine procedures require special patient preparation before the study to obtain the
most accurate result. Pre-imaging preparations may include dietary preparation or the withholding of
certain medications. Patients are encouraged to consult with the nuclear medicine department prior
to a scan.

Analysis[edit]
The end result of the nuclear medicine imaging process is a "dataset" comprising one or more
images. In multi-image datasets the array of images may represent a time sequence (i.e. cine or
movie) often called a "dynamic" dataset, a cardiac gated time sequence, or a spatial sequence
where the gamma-camera is moved relative to the patient. SPECT (single photon emission
computed tomography) is the process by which images acquired from a rotating gamma-camera are
reconstructed to produce an image of a "slice" through the patient at a particular position. A
collection of parallel slices form a slice-stack, a three-dimensional representation of the distribution
of radionuclide in the patient.
The nuclear medicine computer may require millions of lines of source code to provide quantitative
analysis packages for each of the specific imaging techniques available in nuclear medicine.[citation needed]
Time sequences can be further analysed using kinetic models such as multi-compartment models or
a Patlak plot.

Interventional nuclear medicine[edit]

Main articles: Unsealed source radiotherapy and Brachytherapy

Radionuclide therapy can be used to treat conditions such as hyperthyroidism, thyroid cancer, and
blood disorders.
In nuclear medicine therapy, the radiation treatment dose is administered internally (e.g. intravenous
or oral routes) rather than from an external radiation source.
The radiopharmaceuticals used in nuclear medicine therapy emit ionizing radiation that travels only a
short distance, thereby minimizing unwanted side effects and damage to noninvolved organs or
nearby structures. Most nuclear medicine therapies can be performed as outpatient procedures
since there are few side effects from the treatment and the radiation exposure to the general public
can be kept within a safe limit.
Common nuclear medicine (unsealed source) therapies
 Substance Condition

hyperthyroidism and thyroid
Iodine-131-sodium iodide
cancer

Yttrium-90-ibritumomab tiuxetan (Zevalin) and Iodine-131-

refractory lymphoma
tositumomab (Bexxar)

131
I-MIBG (metaiodobenzylguanidine) neuroendocrine tumors

Samarium-153 or Strontium-89 palliative bone pain treatment

In some centers the nuclear medicine department may also use implanted capsules of isotopes
(brachytherapy) to treat cancer.
Commonly used radiation sources (radionuclides) for brachytherapy[3]

Radionuclide Type Half-life Energy

Caesium-137 (137Cs) γ-ray 30.17 years 0.662 MeV

Cobalt-60 (60Co) γ-ray 5.26 years 1.17, 1.33 MeV

Iridium-192 (192Ir) β−-particles 73.8 days 0.38 MeV (mean)

Iodine-125 (125I) γ-rays 59.6 days 27.4, 31.4 and 35.5 keV

Palladium-103 (103Pd) γ-ray 17.0 days 21 keV (mean)

Ruthenium-106 (106Ru) β−-particles 1.02 years 3.54 MeV

History[edit]
The history of nuclear medicine contains contributions from scientists across different disciplines in
physics, chemistry, engineering, and medicine. The multidisciplinary nature of nuclear medicine
makes it difficult for medical historians to determine the birthdate of nuclear medicine. This can
probably be best placed between the discovery of artificial radioactivity in 1934 and the production of
radionuclides by Oak Ridge National Laboratory for medicine related use, in 1946.[4]
The origins of this medical idea date back as far as the mid-1920s in Freiburg, Germany,
when George de Hevesy made experiments with radionuclides administered to rats, thus displaying
metabolic pathways of these substances and establishing the tracer principle. Possibly, the genesis
of this medical field took place in 1936, when John Lawrence, known as "the father of nuclear
medicine", took a leave of absence from his faculty position at Yale Medical School, to visit his
brother Ernest Lawrence at his new radiation laboratory (now known as the Lawrence Berkeley
National Laboratory) in Berkeley, California. Later on, John Lawrence made the first application in
patients of an artificial radionuclide when he used phosphorus-32 to treat leukemia.[5][6]
Many historians consider the discovery of artificially produced radionuclides by Frédéric Joliot-
Curie and Irène Joliot-Curie in 1934 as the most significant milestone in nuclear medicine.[4] In
February 1934, they reported the first artificial production of radioactive material in the
journal Nature, after discovering radioactivity in aluminum foil that was irradiated with a polonium
preparation. Their work built upon earlier discoveries by Wilhelm Konrad Roentgen for X-ray, Henri
Becquerel for radioactive uranium salts, and Marie Curie (mother of Irène Curie) for radioactive
thorium, polonium and coining the term "radioactivity." Taro Takemi studied the application
of nuclear physics to medicine in the 1930s. The history of nuclear medicine will not be complete
without mentioning these early pioneers.
Nuclear medicine gained public recognition as a potential specialty when on May 11,1946 an article
in the Journal of the American Medical Association (JAMA) by Massachusetts General Hospital's
Dr. Saul Hertz and Massachusetts Institute of Technology's Dr.Arthur Roberts, described the
successful use of treating Graves' Disease with radioactive iodine (RAI) was published.
[7]
 Additionally, Sam Seidlin.[8] brought further development in the field describing a successful
treatment of a patient with thyroid cancer metastases using radioiodine (I-131). These articles are
considered by many historians as the most important article ever published in nuclear medicine.
[9]
 Although the earliest use of I-131 was devoted to therapy of thyroid cancer, its use was later
expanded to include imaging of the thyroid gland, quantification of the thyroid function, and therapy
for hyperthyroidism. Among the many radionuclides that were discovered for medical-use, none
were as important as the discovery and development of Technetium-99m. It was first discovered in
1937 by C. Perrier and E. Segre as an artificial element to fill space number 43 in the Periodic Table.
The development of a generator system to produce Technetium-99m in the 1960s became a
practical method for medical use. Today, Technetium-99m is the most utilized element in nuclear
medicine and is employed in a wide variety of nuclear medicine imaging studies.
Widespread clinical use of nuclear medicine began in the early 1950s, as knowledge expanded
about radionuclides, detection of radioactivity, and using certain radionuclides to trace biochemical
processes. Pioneering works by Benedict Cassen in developing the first rectilinear scanner and Hal
O. Anger's scintillation camera (Anger camera) broadened the young discipline of nuclear medicine
into a full-fledged medical imaging specialty.
By the early 1960s, in southern Scandinavia, Niels A. Lassen, David H. Ingvar, and Erik
Skinhøj developed techniques that provided the first blood flow maps of the brain, which initially
involved xenon-133 inhalation;[10] an intra-arterial equivalent was developed soon after, enabling
measurement of the local distribution of cerebral activity for patients with neuropsychiatric disorders
such as schizophrenia.[11] Later versions would have 254 scintillators so a two-dimensional image
could be produced on a color monitor. It allowed them to construct images reflecting brain activation
from speaking, reading, visual or auditory perception and voluntary movement.[12] The technique was
also used to investigate, e.g., imagined sequential movements, mental calculation and mental spatial
navigation.[13][14]
By the 1970s most organs of the body could be visualized using nuclear medicine procedures. In
1971, American Medical Association officially recognized nuclear medicine as a medical specialty.
[15]
 In 1972, the American Board of Nuclear Medicine was established, and in 1974, the American
Osteopathic Board of Nuclear Medicine was established, cementing nuclear medicine as a stand-
alone medical specialty.
In the 1980s, radiopharmaceuticals were designed for use in diagnosis of heart disease. The
development of single photon emission computed tomography (SPECT), around the same time, led
to three-dimensional reconstruction of the heart and establishment of the field of nuclear cardiology.
More recent developments in nuclear medicine include the invention of the first positron emission
tomography scanner (PET). The concept of emission and transmission tomography, later developed
into single photon emission computed tomography (SPECT), was introduced by David E. Kuhl and
Roy Edwards in the late 1950s.[citation needed] Their work led to the design and construction of several
tomographic instruments at the University of Pennsylvania. Tomographic imaging techniques were
further developed at the Washington University School of Medicine. These innovations led to fusion
imaging with SPECT and CT by Bruce Hasegawa from University of California San Francisco
(UCSF), and the first PET/CT prototype by D. W. Townsend from University of Pittsburgh in 1998.
[citation needed]

PET and PET/CT imaging experienced slower growth in its early years owing to the cost of the
modality and the requirement for an on-site or nearby cyclotron. However, an administrative decision
to approve medical reimbursement of limited PET and PET/CT applications in oncology has led to
phenomenal growth and widespread acceptance over the last few years, which also was facilitated
by establishing 18F-labelled tracers for standard procedures, allowing work at non-cyclotron-
equipped sites. PET/CT imaging is now an integral part of oncology for diagnosis, staging and
treatment monitoring. A fully integrated MRI/PET scanner is on the market from early 2011.[citation needed]

Source of radionuclides, with notes on a few

radiopharmaceuticals[edit]
Main article: Radiopharmacology

About a third of the world's supply, and most of Europe's supply, of medical isotopes is produced at
the Petten nuclear reactor in the Netherlands. Another third of the world's supply, and most of North
America's supply, is produced at the Chalk River Laboratories in Chalk River, Ontario, Canada. The
NRU started operating in 1957. The Canadian Nuclear Safety Commission ordered the National
Research Universal reactor to be shut down on November 18, 2007 for regularly scheduled
maintenance and an upgrade of the safety systems to modern standards. The upgrade took longer
than expected, and in December 2007 a critical shortage of medical isotopes occurred. The
Canadian government passed emergency legislation allowing the reactor to restart on 16 December
2007, and production of medical isotopes to continue. In mid-February, 2009, the reactor was shut
down once again due to a mechanism problem that extracts the isotope containing rods from the
reactor. The reactor was again shut down in mid May of the same year because of a heavy water
leak. The reactor was started again during the first quarter of 2010. The NRU will cease routine
production in the fall of 2016, however the reactor will be available for backup production until March
2018, at which point it will be shut down.[16]
The Chalk River reactor is used to irradiate materials with neutrons which are produced in great
quantity during the fission of U-235. These neutrons change the nucleus of the irradiated material by
adding a neutron, or by splitting it in the process of nuclear fission. In a reactor, one of the fission
products of uranium is molybdenum-99 which is extracted and shipped to radiopharmaceutical
houses all over North America. The Mo-99 radioactively beta decays with a half-life of 2.7 days (or
66 hours), turning initially into Tc-99m, which is then extracted (milked) from a "moly cow"
(see technetium-99m generator). The Tc-99m then further decays, while inside a patient, releasing
a gamma photon which is detected by the gamma camera. It decays to its ground state of Tc-99,
which is relatively non-radioactive compared to Tc-99m.
The most commonly used radioisotope in PET F-18, is not produced in any nuclear reactor, but
rather in a circular accelerator called a cyclotron. The cyclotron is used to accelerate protons to
bombard the stable heavy isotope of oxygen O-18. The O-18 constitutes about 0.20% of
ordinary oxygen (mostly O-16), from which it is extracted. The F-18 is then typically used to
make FDG (see this link for more information on this process).

Common isotopes used in nuclear medicine [17][18][19]

isotope symbol Z T1/2 decay gamma (keV) Beta energy (keV)

Imaging:

fluorine-18 18
F 9 109.77 m β+ 511 (193%) 249.8 (97%)[20]

93 (39%),
3
gallium-67 Ga
67
3.26 d ec 185 (21%), -
1
300 (17%)

3
krypton-81m 81m
Kr 13.1 s IT 190 (68%) -
6

3
rubidium-82 82
Rb 1.27 m β+ 511 (191%) 3.379 (95%)
7

nitrogen-13 13
N 7 9.97 m β+ 511 (200%) 1190 (100%)[21]

technetium- 4
99m
Tc 6.01 h IT 140 (89%) -
99m 3

4 171 (90%),
indium-111 111
In 2.80 d ec -
9 245 (94%)

5
iodine-123 123
I 13.3 h ec 159 (83%) -
3
 5
xenon-133 133
Xe 5.24 d β− 81 (31%) 0.364 (99%)
4

8 69–83* (94%),
thallium-201 201
Tl 3.04 d ec -
1 167 (10%)

Therapy:

3
yttrium-90 90
Y 2.67 d β− - 2.280 (100%)
9

5
iodine-131 131
I 8.02 d β− 364 (81%) 0.807 (100%)
3

497 (78.6%),
7 113 (6.6%),
lutetium-177 177
Lu 6.65 d β− 384 (9.1%),
1
208 (11%) 176 (12.2%)

Z = atomic number, the number of protons; T1/2 = half-life; decay = mode of decay
photons = principle photon energies in kilo-electron volts, keV, (abundance/decay)
β = beta maximum energy in mega-electron volts, MeV, (abundance/decay)
β+ = β+ decay; β− = β− decay; IT = isomeric transition; ec = electron capture
* X-rays from progeny, mercury, Hg

A typical nuclear medicine study involves administration of a radionuclide into the body by

intravenous injection in liquid or aggregate form, ingestion while combined with food, inhalation as a
gas or aerosol, or rarely, injection of a radionuclide that has undergone micro-encapsulation. Some
studies require the labeling of a patient's own blood cells with a radionuclide (leukocyte
scintigraphy and red blood cell scintigraphy). Most diagnostic radionuclides emit gamma rays either
directly from their decay or indirectly through electron-positron annihilation, while the cell-damaging
properties of beta particles are used in therapeutic applications. Refined radionuclides for use in
nuclear medicine are derived from fission or fusion processes in nuclear reactors, which produce
radionuclides with longer half-lives, or cyclotrons, which produce radionuclides with shorter half-
lives, or take advantage of natural decay processes in dedicated generators, i.e.
molybdenum/technetium or strontium/rubidium.
The most commonly used intravenous radionuclides are Technetium-99m (technetium-99m), Iodine-
123 and 131, Thallium-201, Gallium-67, Fluorine-18 fluorodeoxyglucose, and Indium-111
Labeled Leukocytes
The most commonly used gaseous/aerosol radionuclides are xenon-133, krypton-81m, Technetium-
99m[22] and technetium-99m DTPA

Radiation dose[edit]
A patient undergoing a nuclear medicine procedure will receive a radiation dose. Under present
international guidelines it is assumed that any radiation dose, however small, presents a risk. The
radiation dose delivered to a patient in a nuclear medicine investigation, though unproven, is
generally accepted to present a very small risk of inducing cancer. In this respect it is similar to the
risk from X-ray investigations except that the dose is delivered internally rather than from an external
source such as an X-ray machine, and dosage amounts are typically significantly higher than those
of X-rays.
The radiation dose from a nuclear medicine investigation is expressed as an effective dose with
units of sieverts (usually given in millisieverts, mSv). The effective dose resulting from an
investigation is influenced by the amount of radioactivity administered in megabecquerels (MBq),
the physical properties of the radiopharmaceutical used, its distribution in the body and its rate of
clearance from the body.
Effective doses can range from 6 μSv (0.006 mSv) for a 3 MBq chromium-51 EDTA measurement of
glomerular filtration rate to 37 mSv (37,000 μSv) for a 150 MBq thallium-201 non-specific tumour
imaging procedure. The common bone scan with 600 MBq of technetium-99m-MDP has an effective
dose of approximately 3.5 mSv (3,500 μSv) (1).
Formerly, units of measurement were the curie (Ci), being 3.7E10 Bq, and also
1.0 grams of Radium (Ra-226); the rad (radiation absorbed dose), now replaced by the gray; and the
rem (Röntgen equivalent man), now replaced with the sievert. The rad and rem are essentially
equivalent for almost all nuclear medicine procedures, and only alpha radiation will produce a higher
Rem or Sv value, due to its much higher Relative Biological Effectiveness (RBE). Alpha emitters are
nowadays rarely used in nuclear medicine, but were used extensively before the advent of nuclear
reactor and accelerator produced radionuclides. The concepts involved in radiation exposure to
humans are covered by the field of Health Physics; the development and practice of safe and
effective nuclear medicinal techniques is a key focus of Medical Physics.

Positron emission tomography

Positron-emission tomography (PET)[1] is a nuclear medicine functional imaging technique that is used to
observe metabolic processes in the body as an aid to the diagnosis of disease. The system detects pairs
of gamma rays emitted indirectly by a positron-emitting radioligand, most commonly fluorine-18, which is
introduced into the body on a biologically active molecule called a radioactive tracer. Different ligands are
used for different imaging purposes, depending on what the radiologist/researcher wants to detect. Three-
dimensional images of tracer concentration within the body are then constructed by computer analysis. In
modern PET computed tomography scanners, three-dimensional imaging is often accomplished with the aid of
a computed tomography X-ray scan performed on the patient during the same session, in the same machine.
If the biologically active tracer molecule chosen for PET is fludeoxyglucose (FDG), an analogue of glucose,
the concentrations of tracer imaged will indicate tissue metabolic activity as it corresponds to the regional
glucose uptake. Use of this tracer to explore the possibility of cancer metastasis (i.e., spreading to other sites)
is the most common type of PET scan in standard medical care (representing 90% of current scans). Metabolic
trapping of the radioactive glucose molecule allows the PET scan to be utilized.[2] The same tracer may also be
used for PET investigation and diagnosis of types of dementia. Less often, other radioactive tracers, usually
but not always labeled with fluorine-18, are used to image the tissue concentration of other types of molecules
of interest.
One of the disadvantages of PET scanners is their operating cost.[3] A similar imaging process to PET is single-
photon emission computed tomography (SPECT), which also uses radioligands to detect molecules in the
brain, and is less expensive.

Uses

PET/CT-System with 16-slice CT; the ceiling mounted device is an injection pump for CT contrast agent

PET is both a medical and research tool. It is used heavily in clinical oncology (medical

imaging of tumours and the search for metastases), and for clinical diagnosis of certain diffuse brain
diseases such as those causing various types of dementias. PET is also an important research tool
to map normal human brain and heart function, and support drug development.
PET is also used in pre-clinical studies using animals, where it allows repeated investigations into
the same subjects. This is particularly valuable in cancer research, as it results in an increase in the
statistical quality of the data (subjects can act as their own control) and substantially reduces the
numbers of animals required for a given study.
Alternative methods of scanning include x-ray computed tomography (CT), magnetic resonance
imaging (MRI) and functional magnetic resonance imaging (fMRI), ultrasound and single-photon
emission computed tomography (SPECT).
While some imaging scans such as CT and MRI isolate organic anatomic changes in the body, PET
and SPECT are capable of detecting areas of molecular biology detail (even prior to anatomic
change). PET scanning does this using radiolabelled molecular probes that have different rates of
uptake depending on the type and function of tissue involved. Changing of regional blood flow in
various anatomic structures (as a measure of the injected positron emitter) can be visualized and
relatively quantified with a PET scan.
PET imaging is best performed using a dedicated PET scanner. It is also possible to acquire PET
images using a conventional dual-head gamma camera fitted with a coincidence detector. Although
the quality of gamma-camera PET is considerably lower and acquisition is slower, this method
allows institutions with low demand for PET to provide on-site imaging, instead of referring patients
to another centre or relying on a visit by a mobile scanner.

Oncology

Whole-body PET scan using 18F-FDG. The normal brain and kidneys are labeled, and radioactive urine from
breakdown of the FDG is seen in the bladder. In addition, a large metastatic tumor mass from colon cancer is
seen in the liver.

PET scanning with the tracer fluorine-18 (F-18) fluorodeoxyglucose (FDG), called FDG-PET, is

widely used in clinical oncology. This tracer is a glucose analog that is taken up by glucose-using
cells and phosphorylated by hexokinase (whose mitochondrial form is greatly elevated in rapidly
growing malignant tumors). A typical dose of FDG used in an oncological scan has an effective
radiation dose of 7.6 mSv.[4] Because the oxygen atom that is replaced by F-18 to generate FDG is
required for the next step in glucose metabolism in all cells, no further reactions occur in FDG.
Furthermore, most tissues (with the notable exception of liver and kidneys) cannot remove
the phosphate added by hexokinase. This means that FDG is trapped in any cell that takes it up until
it decays, since phosphorylated sugars, due to their ionic charge, cannot exit from the cell. This
results in intense radiolabeling of tissues with high glucose uptake, such as the normal brain, liver,
kidneys, and most cancers. As a result, FDG-PET can be used for diagnosis, staging, and
monitoring treatment of cancers, particularly in Hodgkin's lymphoma, non-Hodgkin lymphoma,
and lung cancer.[citation needed]
A few other isotopes and radiotracers are slowly being introduced into oncology for specific
purposes. For example, 11C-labelled metomidate (11C-metomidate), has been used to detect tumors
of adrenocortical origin.[5][6] Also, FDOPA PET/CT (or F-18-DOPA PET/CT), in centers which offer it,
has proven to be a more sensitive alternative to finding, and also localizing, pheochromocytoma than
the MIBG scan.[7][8][9]

Neuroimaging
Main article: Brain positron emission tomography

PET scan of the human brain

● Neurology: PET neuroimaging is based on an assumption that areas of high radioactivity are

associated with brain activity. What is actually measured indirectly is the flow of blood to
different parts of the brain, which is, in general, believed to be correlated, and has been
measured using the tracer oxygen-15. Because of its 2-minute half-life, O-15 must be piped
directly from a medical cyclotron for such uses, which is difficult.
o Example: In practice, since the brain is normally a rapid user of glucose, and since brain
pathologies such as Alzheimer's disease greatly decrease brain metabolism of both
glucose and oxygen in tandem, standard FDG-PET of the brain, which measures regional
glucose use, may also be successfully used to differentiate Alzheimer's disease from other
dementing processes, and also to make early diagnoses of Alzheimer's disease. The
advantage of FDG-PET for these uses is its much wider availability. Some radioactive
tracers used for Alzheimer's are florbetapir F18, flutemetamol F18, and florbetabenF18,
which are all used to detect amyloid-beta plaques (a potential biomarker for Alzheimer's) in
the brain.
o Examples: PET imaging with FDG can also be used for localization of seizure focus: A
seizure focus will appear as hypometabolic during an interictal scan.
Several radiotracers (i.e. radioligands) have been developed for PET that are ligands for
specific neuroreceptor subtypes such as [11C] raclopride, [18F] fallypride and
[18F] desmethoxyfallypride for dopamine D2/D3 receptors, [11C] McN 5652 and
[11C] DASB for serotonin transporters, [18F] Mefway for serotonin 5HT1A receptors,
[18F] Nifene for nicotinic acetylcholine receptors or enzyme substrates (e.g. 6-FDOPA for
the AADC enzyme). These agents permit the visualization of neuroreceptor pools in the
context of a plurality of neuropsychiatric and neurologic illnesses.
The development of a number of novel probes for noninvasive, in vivo PET imaging of
neuroaggregate in human brain has brought amyloid imaging to the doorstep of clinical use.
The earliest amyloid imaging probes included 2-(1-{6-[(2-[18F]fluoroethyl)(methyl)amino]-2-
naphthyl}ethylidene)malononitrile ([18F]FDDNP)[10] developed at the University of California,
Los Angeles and N-methyl-[11C]2-(4'-methylaminophenyl)-6-
hydroxybenzothiazole[11] (termed Pittsburgh compound B) developed at the University of
Pittsburgh. These amyloid imaging probes permit the visualization of amyloid plaques in the
brains of Alzheimer's patients and could assist clinicians in making a positive clinical
diagnosis of AD pre-mortem and aid in the development of novel anti-amyloid therapies.
 [11C]PMP (N-[11C]methylpiperidin-4-yl propionate) is a novel radiopharmaceutical used in PET
imaging to determine the activity of the acetylcholinergic neurotransmitter system by acting
as a substrate for acetylcholinesterase. Post-mortem examination of AD patients have
shown decreased levels of acetylcholinesterase. [11C]PMP is used to map the
acetylcholinesterase activity in the brain, which could allow for pre-mortem diagnoses of AD
and help to monitor AD treatments.[12] Avid Radiopharmaceuticals has developed and
commercialized a compound called florbetapir that uses the longer-lasting
radionuclide fluorine-18 to detect amyloid plaques using PET scans.[13]

● Neuropsychology / Cognitive neuroscience: To examine links between specific

psychological processes or disorders and brain activity.
● Psychiatry: Numerous compounds that bind selectively to neuroreceptors of interest in
biological psychiatry have been radiolabeled with C-11 or F-18. Radioligands that bind
to dopamine receptors (D1,[14] D2 receptor,[15][16] reuptake transporter), serotonin
receptors (5HT1A, 5HT2A, reuptake transporter) opioid receptors (mu) and other sites have
been used successfully in studies with human subjects. Studies have been performed
examining the state of these receptors in patients compared to healthy controls
in schizophrenia, substance abuse, mood disorders and other psychiatric conditions.
● Stereotactic surgery and radiosurgery: PET-image guided surgery facilitates treatment of
intracranial tumors, arteriovenous malformations and other surgically treatable conditions.[17]
Cardiology
Main article: Cardiac PET

Cardiology, atherosclerosis and vascular disease study: In clinical cardiology, FDG-PET can

identify so-called "hibernating myocardium", but its cost-effectiveness in this role
versus SPECT is unclear. FDG-PET imaging of atherosclerosis to detect patients at risk
of stroke is also feasible and can help test the efficacy of novel anti-atherosclerosis therapies.[18]

Infectious diseases
Imaging infections with molecular imaging technologies can improve diagnosis and treatment
follow-up. PET has been widely used to image bacterial infections clinically by
using fluorodeoxyglucose (FDG) to identify the infection-associated inflammatory response.
Three different PET contrast agents have been developed to image bacterial infections in vivo:
[18F]maltose,[19] [18F]maltohexaose and [18F]2-fluorodeoxysorbitol (FDS).[20] FDS has also the added
benefit of being able to target only Enterobacteriaceae.

Pharmacokinetics
Pharmacokinetics: In pre-clinical trials, it is possible to radiolabel a new drug and inject it into
animals. Such scans are referred to as biodistribution studies. The uptake of the drug, the
tissues in which it concentrates, and its eventual elimination, can be monitored far more quickly
and cost effectively than the older technique of killing and dissecting the animals to discover the
same information. Much more commonly, drug occupancy at a purported site of action can be
inferred indirectly by competition studies between unlabeled drug and radiolabeled compounds
known apriori to bind with specificity to the site. A single radioligand can be used this way to test
many potential drug candidates for the same target. A related technique involves scanning with
radioligands that compete with an endogenous (naturally occurring) substance at a given
receptor to demonstrate that a drug causes the release of the natural substance.[21]
Small animal imaging
PET technology for small animal imaging: A miniature PE tomograph has been constructed that
is small enough for a fully conscious and mobile rat to wear on its head while walking around.
[22]
 This RatCAP (Rat Conscious Animal PET) allows animals to be scanned without the
confounding effects of anesthesia. PET scanners designed specifically for imaging rodents,
often referred to as microPET, as well as scanners for small primates, are marketed for
academic and pharmaceutical research. The scanners are apparently based on microminiature
scintillators and amplified avalanche photodiodes (APDs) through a new system recently
invented uses single chip silicon photomultipliers.[citation needed]
In 2018 the UC Davis School of Veterinary Medicine became the first veterinary center to
employ a small clinical PET-scanner as a pet-PET scan, for clinical (rather than research)
animal diagnosis. Because of cost as well as the marginal utility of detecting cancer metastases
in companion animals (the primary use of this modality), veterinary PET scanning is expected to
be rarely available in the immediate future.[23]

Musculo-skeletal imaging
Musculoskeletal imaging: PET has been shown to be a feasible technique for studying skeletal
muscles during exercises like walking.[24] One of the main advantages of using PET is that it can
also provide muscle activation data about deeper lying muscles such as the vastus
intermedialis and the gluteus minimus, as compared to other muscle studying techniques
like electromyography, which can be used only on superficial muscles (i.e., directly under the
skin). A clear disadvantage is that PET provides no timing information about muscle activation
because it has to be measured after the exercise is completed. This is due to the time it takes
for FDG to accumulate in the activated muscles.

Safety
PET scanning is non-invasive, but it does involve exposure to ionizing radiation.[3]
18F-FDG, which is now the standard radiotracer used for PET neuroimaging and cancer patient
management,[25] has an effective radiation dose of 14 mSv.[4]
The amount of radiation in 18F-FDG is similar to the effective dose of spending one year in the
American city of Denver, Colorado (12.4 mSv/year).[26] For comparison, radiation dosage for
other medical procedures range from 0.02 mSv for a chest x-ray and 6.5–8 mSv for a CT scan
of the chest.[27][28] Average civil aircrews are exposed to 3 mSv/year,[29] and the whole body
occupational dose limit for nuclear energy workers in the USA is 50mSv/year.[30] For scale,
see Orders of magnitude (radiation).
For PET-CT scanning, the radiation exposure may be substantial—around 23–26 mSv (for a
70 kg person—dose is likely to be higher for higher body weights).[31]

Operation
Radionuclides and radiotracers
Main articles: List of PET radiotracers and Fludeoxyglucose
Schematic view of a detector block and ring of a PET scanner

Radionuclides used in PET scanning are typically isotopes with short half-lives[3] such as carbon-

11 (~20 min), nitrogen-13 (~10 min), oxygen-15 (~2 min), fluorine-18 (~110 min), gallium-
68 (~67 min), zirconium-89 (~78.41 hours),[32] or rubidium-82(~1.27 min). These radionuclides
are incorporated either into compounds normally used by the body such as glucose (or glucose
analogues), water, or ammonia, or into molecules that bind to receptors or other sites of drug
action. Such labelled compounds are known as radiotracers. PET technology can be used to
trace the biologic pathway of any compound in living humans (and many other species as well),
provided it can be radiolabeled with a PET isotope. Thus, the specific processes that can be
probed with PET are virtually limitless, and radiotracers for new target molecules and processes
are continuing to be synthesized; as of this writing there are already dozens in clinical use and
hundreds applied in research. At present,[when?] by far the most commonly used radiotracer in
clinical PET scanning is fluorodeoxyglucose (also called FDG or fludeoxyglucose), an analogue
of glucose that is labeled with fluorine-18. This radiotracer is used in essentially all scans for
oncology and most scans in neurology, and thus makes up the large majority of all of the
radiotracer (> 95%) used in PET and PET-CT scanning.
Due to the short half-lives of most positron-emitting radioisotopes, the radiotracers have
traditionally been produced using a cyclotron in close proximity to the PET imaging facility. The
half-life of fluorine-18 is long enough that radiotracers labeled with fluorine-18 can be
manufactured commercially at offsite locations and shipped to imaging centers.
Recently rubidium-82 generators have become commercially available.[33] These contain
strontium-82, which decays by electron capture to produce positron-emitting rubidium-82.

Emission

Schema of a PET acquisition process

To conduct the scan, a short-lived radioactive tracer isotope is injected into the living subject
(usually into blood circulation). Each tracer atom has been chemically incorporated into a
biologically active molecule. There is a waiting period while the active molecule becomes
concentrated in tissues of interest; then the subject is placed in the imaging scanner. The
molecule most commonly used for this purpose is F-18 labeled fluorodeoxyglucose (FDG), a
sugar, for which the waiting period is typically an hour. During the scan, a record of tissue
concentration is made as the tracer decays.
As the radioisotope undergoes positron emission decay (also known as positive beta decay), it
emits a positron, an antiparticle of the electron with opposite charge. The emitted positron
travels in tissue for a short distance (typically less than 1 mm, but dependent on the isotope[34]),
during which time it loses kinetic energy, until it decelerates to a point where it can interact with
an electron.[35] The encounter annihilates both electron and positron, producing a pair
of annihilation (gamma) photons moving in approximately opposite directions. These are
detected when they reach a scintillator in the scanning device, creating a burst of light which is
detected by photomultiplier tubes or silicon avalanche photodiodes (Si APD). The technique
depends on simultaneous or coincident detection of the pair of photons moving in approximately
opposite directions (they would be exactly opposite in their center of mass frame, but the
scanner has no way to know this, and so has a built-in slight direction-error tolerance). Photons
that do not arrive in temporal "pairs" (i.e. within a timing-window of a few nanoseconds) are
ignored.

Localization of the positron annihilation event

The most significant fraction of electron–positron annihilations results in two 511 keV gamma
photons being emitted at almost 180 degrees to each other; hence, it is possible to localize their
source along a straight line of coincidence (also called the line of response, or LOR). In
practice, the LOR has a non-zero width as the emitted photons are not exactly 180 degrees
apart. If the resolving time of the detectors is less than 500 picoseconds rather than about
10 nanoseconds, it is possible to localize the event to a segment of a chord, whose length is
determined by the detector timing resolution. As the timing resolution improves, the signal-to-
noise ratio (SNR) of the image will improve, requiring fewer events to achieve the same image
quality. This technology is not yet common, but it is available on some new systems.[36]

Image reconstruction
The raw data collected by a PET scanner are a list of 'coincidence events' representing near-
simultaneous detection (typically, within a window of 6 to 12 nanoseconds of each other) of
annihilation photons by a pair of detectors. Each coincidence event represents a line in space
connecting the two detectors along which the positron emission occurred (i.e., the line of
response (LOR)).
Analytical techniques, much like the reconstruction of computed tomography (CT) and single-
photon emission computed tomography (SPECT) data, are commonly used, although the data
set collected in PET is much poorer than CT, so reconstruction techniques are more difficult.
Coincidence events can be grouped into projection images, called sinograms. The sinograms
are sorted by the angle of each view and tilt (for 3D images). The sinogram images are
analogous to the projections captured by computed tomography (CT) scanners, and can be
reconstructed in a similar way. The statistics of data thereby obtained are much worse than
those obtained through transmission tomography. A normal PET data set has millions of counts
for the whole acquisition, while the CT can reach a few billion counts. This contributes to PET
images appearing "noisier" than CT. Two major sources of noise in PET are scatter (a detected
pair of photons, at least one of which was deflected from its original path by interaction with
matter in the field of view, leading to the pair being assigned to an incorrect LOR) and random
events (photons originating from two different annihilation events but incorrectly recorded as a
coincidence pair because their arrival at their respective detectors occurred within a coincidence
timing window).
In practice, considerable pre-processing of the data is required—correction for random
coincidences, estimation and subtraction of scattered photons, detector dead-time correction
(after the detection of a photon, the detector must "cool down" again) and detector-sensitivity
correction (for both inherent detector sensitivity and changes in sensitivity due to angle of
incidence).
Filtered back projection (FBP) has been frequently used to reconstruct images from the
projections. This algorithm has the advantage of being simple while having a low requirement for
computing resources. Disadvantages are that shot noise in the raw data is prominent in the
reconstructed images, and areas of high tracer uptake tend to form streaks across the image.
Also, FBP treats the data deterministically—it does not account for the inherent randomness
associated with PET data, thus requiring all the pre-reconstruction corrections described above.
Statistical, likelihood-based approaches: Statistical, likelihood-based [37]
[38]
 iterative expectation-maximization algorithms such as the Shepp-Vardi algorithm[39] are now
the preferred method of reconstruction. These algorithms compute an estimate of the likely
distribution of annihilation events that led to the measured data, based on statistical principles.
The advantage is a better noise profile and resistance to the streak artifacts common with FBP,
but the disadvantage is higher computer resource requirements. A further advantage of
statistical image reconstruction techniques is that the physical effects that would need to be pre-
corrected for when using an analytical reconstruction algorithm, such as scattered photons,
random coincidences, attenuation and detector dead-time, can be incorporated into the
likelihood model being used in the reconstruction, allowing for additional noise reduction.
Iterative reconstruction has also been shown to result in improvements in the resolution of the
reconstructed images, since more sophisticated models of the scanner Physics can be
incorporated into the likelihood model than those used by analytical reconstruction methods,
allowing for improved quantification of the radioactivity distribution.[40]
Research has shown that Bayesian methods that involve a Poisson likelihood function and an
appropriate prior probability (e.g., a smoothing prior leading to total variation regularization or

a Laplacian distribution leading to  -based regularization in a wavelet or other domain), such

as via Ulf Grenander's Sieve estimator[41][42] or via Bayes penalty methods[43][44] or via I.J. Good's
roughness method[45][46] may yield superior performance to expectation-maximization-based
methods which involve a Poisson likelihood function but do not involve such a prior.[47][48][49]
Attenuation correction: Quantitative PET Imaging requires attenuation correction.[50] In these
systems attenuation correction is based on a transmission scan using 68Ge rotating rod source.[51]
transmission scans directly measure attenuation values at 511keV.[52] Attenuation occurs
when photons emitted by the radiotracer inside the body are absorbed by intervening tissue
between the detector and the emission of the photon. As different LORs must traverse different
thicknesses of tissue, the photons are attenuated differentially. The result is that structures deep
in the body are reconstructed as having falsely low tracer uptake. Contemporary scanners can
estimate attenuation using integrated x-ray CT equipment, in place of earlier equipment that
offered a crude form of CT using a gamma ray (positron emitting) source and the PET detectors.
While attenuation-corrected images are generally more faithful representations, the correction
process is itself susceptible to significant artifacts. As a result, both corrected and uncorrected
images are always reconstructed and read together.
2D/3D reconstruction: Early PET scanners had only a single ring of detectors, hence the
acquisition of data and subsequent reconstruction was restricted to a single transverse plane.
More modern scanners now include multiple rings, essentially forming a cylinder of detectors.
There are two approaches to reconstructing data from such a scanner: 1) treat each ring as a
separate entity, so that only coincidences within a ring are detected, the image from each ring
can then be reconstructed individually (2D reconstruction), or 2) allow coincidences to be
detected between rings as well as within rings, then reconstruct the entire volume together (3D).
3D techniques have better sensitivity (because more coincidences are detected and used) and
therefore less noise, but are more sensitive to the effects of scatter and random coincidences,
as well as requiring correspondingly greater computer resources. The advent of sub-
nanosecond timing resolution detectors affords better random coincidence rejection, thus
favoring 3D image reconstruction.
Time-of-flight (TOF) PET: For modern systems with a higher time resolution (roughly 3
nanoseconds) a technique called "Time-of-flight" is used to improve the overall performance.
Time-of-flight PET makes use of very fast gamma-ray detectors and data processing system
which can more precisely decide the difference in time between the detection of the two
photons. Although it is technically impossible to localize the point of origin of the annihilation
event exactly (currently within 10 cm) thus image reconstruction is still needed, TOF technique
gives a remarkable improvement in image quality, especially signal-to-noise ratio.

Combination of PET with CT or MRI

Main articles: PET-CT and PET-MRI

Complete body PET-CT fusion image

Brain PET-MRI fusion image

PET scans are increasingly read alongside CT or magnetic resonance imaging (MRI) scans,
with the combination (called "co-registration") giving both anatomic and metabolic information
(i.e., what the structure is, and what it is doing biochemically). Because PET imaging is most
useful in combination with anatomical imaging, such as CT, modern PET scanners are now
available with integrated high-end multi-detector-row CT scanners (so-called "PET-CT").
Because the two scans can be performed in immediate sequence during the same session, with
the patient not changing position between the two types of scans, the two sets of images are
more precisely registered, so that areas of abnormality on the PET imaging can be more
perfectly correlated with anatomy on the CT images. This is very useful in showing detailed
views of moving organs or structures with higher anatomical variation, which is more common
outside the brain.
At the Jülich Institute of Neurosciences and Biophysics, the world's largest PET-MRI device
began operation in April 2009: a 9.4-tesla magnetic resonance tomograph (MRT) combined with
a positron emission tomograph (PET). Presently, only the head and brain can be imaged at
these high magnetic field strengths.[53]
For brain imaging, registration of CT, MRI and PET scans may be accomplished without the
need for an integrated PET-CT or PET-MRI scanner by using a device known as the N-localizer.
[17][54][55][56]

Limitations
The minimization of radiation dose to the subject is an attractive feature of the use of short-lived
radionuclides. Besides its established role as a diagnostic technique, PET has an expanding
role as a method to assess the response to therapy, in particular, cancer therapy,[57] where the
risk to the patient from lack of knowledge about disease progress is much greater than the risk
from the test radiation. Since the tracers are radioactive, the elderly and pregnant are unable to
use it due to risks posed by radiation.
Limitations to the widespread use of PET arise from the high costs of cyclotrons needed to
produce the short-lived radionuclides for PET scanning and the need for specially adapted on-
site chemical synthesis apparatus to produce the radiopharmaceuticals after radioisotope
preparation. Organic radiotracer molecules that will contain a positron-emitting radioisotope
cannot be synthesized first and then the radioisotope prepared within them, because
bombardment with a cyclotron to prepare the radioisotope destroys any organic carrier for it.
Instead, the isotope must be prepared first, then afterward, the chemistry to prepare any organic
radiotracer (such as FDG) accomplished very quickly, in the short time before the isotope
decays. Few hospitals and universities are capable of maintaining such systems, and most
clinical PET is supported by third-party suppliers of radiotracers that can supply many sites
simultaneously. This limitation restricts clinical PET primarily to the use of tracers labelled with
fluorine-18, which has a half-life of 110 minutes and can be transported a reasonable distance
before use, or to rubidium-82 (used as rubidium-82 chloride) with a half-life of 1.27 minutes,
which is created in a portable generator and is used for myocardial perfusion studies.
Nevertheless, in recent years a few on-site cyclotrons with integrated shielding and "hot labs"
(automated chemistry labs that are able to work with radioisotopes) have begun to accompany
PET units to remote hospitals. The presence of the small on-site cyclotron promises to expand
in the future as the cyclotrons shrink in response to the high cost of isotope transportation to
remote PET machines.[58] In recent years the shortage of PET scans has been alleviated in the
US, as rollout of radiopharmacies to supply radioisotopes has grown 30%/year.[59]
Because the half-life of fluorine-18 is about two hours, the prepared dose of a
radiopharmaceutical bearing this radionuclide will undergo multiple half-lives of decay during the
working day. This necessitates frequent recalibration of the remaining dose (determination of
activity per unit volume) and careful planning with respect to patient scheduling.

History
The concept of emission and transmission tomography was introduced by David E. Kuhl, Luke
Chapman and Roy Edwards in the late 1950s. Their work later led to the design and
construction of several tomographic instruments at the University of Pennsylvania. In 1975
tomographic imaging techniques were further developed by Michel Ter-Pogossian, Michael E.
Phelps, Edward J. Hoffman and others at Washington University School of Medicine.[60][61]
Work by Gordon Brownell, Charles Burnham and their associates at the Massachusetts General
Hospital beginning in the 1950s contributed significantly to the development of PET technology
and included the first demonstration of annihilation radiation for medical imaging.[62] Their
innovations, including the use of light pipes and volumetric analysis, have been important in the
deployment of PET imaging. In 1961, James Robertson and his associates at Brookhaven
National Laboratory built the first single-plane PET scan, nicknamed the "head-shrinker."[63]
One of the factors most responsible for the acceptance of positron imaging was the
development of radiopharmaceuticals. In particular, the development of labeled 2-fluorodeoxy-D-
glucose (2FDG) by the Brookhaven group under the direction of Al Wolf and Joanna Fowler was
a major factor in expanding the scope of PET imaging.[64] The compound was first administered
to two normal human volunteers by Abass Alavi in August 1976 at the University of
Pennsylvania. Brain images obtained with an ordinary (non-PET) nuclear scanner demonstrated
the concentration of FDG in that organ. Later, the substance was used in dedicated positron
tomographic scanners, to yield the modern procedure.
The logical extension of positron instrumentation was a design using two 2-dimensional arrays.
PC-I was the first instrument using this concept and was designed in 1968, completed in 1969
and reported in 1972. The first applications of PC-I in tomographic mode as distinguished from
the computed tomographic mode were reported in 1970.[65] It soon became clear to many of
those involved in PET development that a circular or cylindrical array of detectors was the logical
next step in PET instrumentation. Although many investigators took this approach, James
Robertson[66] and Zang-Hee Cho[67] were the first to propose a ring system that has become the
prototype of the current shape of PET.
The PET-CT scanner, attributed to Dr. David Townsend and Dr. Ronald Nutt, was named by
TIME Magazine as the medical invention of the year in 2000.[68]