History and Development of PET

Elaine H. Wacholtz, Ph.D.

InTroDucTIon

Positron emission tomography (PET) is a noninvasive diagnostic imaging procedure that enables medical professionals to view the human body’s biological functions and to study disease processes. Until recently, PET had been envisioned and employed as a research tool, particularly in the study of neurophysiology. In the last decade, however, the clinical value of PET as an imaging modality has become increasingly apparent. Medical professionals in the fields of oncology, cardiology, and neurology have been using PET techniques to assess metabolism in their respective evaluations of cancer, damaged heart tissue, and brain disorders. Expectations are high that PET, a nuclear medicine scanning procedure that employs positron-emitting radioactive isotopes to image the body’s metabolic activity, will add a new dimension to the evaluation and treatment planning of a variety of diseases and medical conditions and that it will serve as a valuable tool for patients’ follow-up and care. 1-3

During the PET scanning procedure, physicians and researchers are able to measure in detail the functioning of the human brain [how it thinks and remembers] and other organs [how the heart beats and how the pancreas synthesizes insulin, for example] while patients remain comfortable, conscious, and alert. The PET scanner generates three-dimensional images of the distribution of an IV-administered radiopharmaceutical (a substance containing a carrier molecule, such as glucose, and a positron-emitting radioactive isotope that labels the carrier molecule) within the body. The images enable evaluation of physiologic phenomena that include glucose metabolism, oxygen metabolism, cerebral blood f low, and receptor sites in the brain. Before the advent of the PET scanner, the study of such physiologic phenomena was not possible. During those times, what went on in patients’ organs and body systems when they were afflicted with disease and illness was inferred from post-mortem dis- sections or from animal studies? 4-5

PET extends the capabilities of other diagnostic imaging procedures, such as magnetic resonance imaging (MRI) and computed tomography (CT). Like these procedures, PET uses tomographic algorithms to display data as cross-sectional images in any plane of the living human body. And, as is the case in other nuclear medicine procedures, PET’s images are derived from the distribution of radiopharmaceuticals in the body. These two similarities represent the extent of PET’s likeness to MRI and CT and the beginning of its uniqueness. PET’s uniqueness thrives on its ability to produce functional images that permit assessment of chemical and physiological changes associated with metabolic activity, in comparison to the anatomical images produced by MRI and CT that largely depict structure and shape. 1

In the first section of this article, we examine in a com- prehensive way PET’s historical perspective, we delve into the reasons for its recent progression in the clinical sector, and we present the year 2000 medical imaging innovation that has combined PET and CT technologies, the PET/CT scanner. In the second section, we explore how PET works by looking briefly at the physics behind the process and what the patient experiences.

HIsTorIcal PErsPEcTIvE

Early BEgInnIngs

CT has been viewed by some as a harbinger paving the way for the emergence of PET. Such a view seems quite logical since both CT and PET are diagnostic imaging procedures and since CT came first and PET has fol- lowed, making its own technologically-advanced debut. It is important to keep in mind that such a view could possibly lose sight of some of the antecedent features particular to PET, such as the group of radioisotopes with short half-lives on which PET is based, a positron-emitting decay scheme, the gamma camera or scanner, and chemical properties with apparent relevance to studies in biology and medicine. What is interesting about these features is that they were being studied by promi- nent investigators before CT came into being. One such investigator was Ernest O. Lawrence, who in the early 1930s in his University-of-California-at-Berkley laboratory invented the cyclotron. As the research of E.O.

Lawrence and his colleagues progressed, their cyclotrons increased in size and efficiency and they produced and identified a number of short-lived radioisotopes, such as Carbon-11, Nitrogen-13, Oxygen-15, and Fluorine-18, each of which is currently being used in the synthesis of PET radiopharmaceuticals.

THE 1950s—PIonEErIng IDEas for PET

Wartime research in the late 1930s led to the development of the nuclear reactor, which, unfortunately, temporarily retired the use of Lawrence and colleagues’ cyclotron and led to use of reactor-produced radioisotopes (because they were more easily and less expen- sively produced than the short-lived, cyclotron-produced radioisotopes) in the 1940s for biomedical research. The early 1950s heralded two inventions and investigators that contributed to the emergence of imaging in nuclear medicine: the rectilinear scanner by Benedict Cassen and colleagues at UCLA and the gamma camera by Hal Anger and colleagues in Berkeley, California. In 1953, Gordon Brownell at MIT created a precursor to the up- and-coming PET scanner when he constructed the first detector device to record the annihilation that occurs when positrons from positron-emitting pharmaceuticals collide with electrons in the human body. In the middle 1950s, Michel Ter-Pogossian and William Powers of Washington University’s Mallinckrodt Institute of Radiology reinstated in biomedical research the use of radiopharmaceuticals labeled with short-lived, cyclotron- produced radioisotopes. At about this time (1955) on the other side of the world, the first medical cyclotron was built at Hammersmith Hospital in London. Successful experimentation at Hammersmith Hospital led to installation of a National Institutes of Health (NIH)-funded cyclotron in Washington University Medical Center, fol- lowed by the Department of Energy’s funding of hospital cyclotrons at UCLA, University of Chicago, and Memorial Sloan Kettering Institute in New York. And, so the production of radioisotopes continued with the use of cyclotrons at these hospitals as well as with the use of existing cyclotrons at UC Berkley and Ohio State. Another development that contributed to the emergence of PET was CT, which was invented by Alan Cormack and Godfrey Hounsfield and popularized by investigator, David Kuhl, and colleagues at the University of Pennsylvania in 1959.

THE 1960s anD 1970s—THE DEvEloPmEnT of PET

During the late 1960s, Ter-Pogossian and colleagues continued with and advanced their studies using radioisotope/radiopharmaceutical techniques while Kuhl and colleagues persevered in their studies of emission computed tomography and built the Mark II scanner, often referred to as the ancestor to today’s CT and SPECT scanners. Kuhl and colleagues also studied reconstruc-

tion algorithms, but it was David Chesler’s filtered back projection technique originally developed for CT that was ultimately modified and applied to PET.

The modification and application of Chesler’s filtered back projection technique to PET together with the apt readiness of Ter-Pogossian’s laboratory (i.e., positron- emitting radioisotopes, experience in their production, computers with which to implement algorithms, and engineering expertise in cyclotron targetry, detector systems, and imaging devices), the youthful enthusiasm and workmanship of Michael E. Phelps and his team of colleagues [i.e., Jerry Cox and Edward Hoffman], and the support of the Department of Energy and NIH paved the way for the 1974 development of the first PET camera or scanner, the PETT III. The star feature of the PETT III was its ability to use advanced algorithms for computing three-dimensional images, which according to today’s standard of PET images, were crude. The PETT III was, for the most part, limited to imaging the head and its resolution was only about 20 mm. In addition to his being one of the developers of the first PET scanner built for human studies, Phelps has contributed to the proliferation of PET into the clinical sector by engineering the design of cancer-imaging applications, aiding in the development of PET whole-body scans, establishing the first clinical PET services at UCLA Medical Center in 1990, and heading the international transition of PET from research to clinical application. 6

Other developments that were essential to the emergence of PET included studies of functional brain mapping in animals, which alerted neuroscientists about the information that could be derived from measuring brain blood f low and metabolism, and studies of the decay scheme of positron-emitting radioisotopes. It was in the 1970s that researchers realized that highly accurate measurement of brain function in humans could be performed with PET and that the most favored technique was blood f low because it could be measured quickly with the radiopharmaceutical, O-15 water, whose short half-life of two minutes made it possible to safely repeat numerous measurements in the same subject.

When they were first introduced in the U.S. in 1970, PET scanners were viewed as a new and exciting research modality that enabled medical researchers to observe, study, and understand the biology of human disease. In 1976 using an application evolved from the work of Louis Sokoloff and colleagues, Al Wolf and Joanna Fowler, chemists at Brookhaven National Laboratory, developed the radiopharmaceutical, fluorodeoxyglucose with Fluorine-18 (FDG)-a development that laid the ground- work for more in-depth research and did much to expand the scope of PET imaging.

It is interesting to note that the performance of PET studies in the late 1970s was a cumbersome and expensive venture because the procedure required costly, on-site equipment that included a cyclotron for the manufacture of radioisotopes, a synthesizing unit for the biosynthesis It is interesting to note that the performance of PET studies in the late 1970s was a cumbersome and expensive venture because the procedure required costly, on-site equipment that included a cyclotron for the manufacture of radioisotopes, a synthesizing unit for the biosynthesis

to nearby hospitals and clinics for use in PET imaging-in component of the radiopharmaceutical, as well as a large

much the same way as conventional radiopharmaceuticals staff comprised of physicists to operate the cyclotron and

are distributed by nuclear medicine radiopharmacies. At oversee the scanner, chemists to synthesize radiophar-

the time of a 2000 publication of UCLA’s Technology maceuticals (such as FDG), and dedicated, specializing

Overview, there were over 60 PET radiopharmacies physicians to interpret and analyze the images. The first

in the world responsible for the production, chemistry, PET scan of a human was reported in 1978. 7 quality assurance, and business management of PET

The 1970s are seen as the decade in which the devel- radiopharmaceuticals, of which FDG was the most opment of PET took place and grew to become a widely

widely used. All of this is now possible without the tech- encompassing research modality whose impact enabled

nical, logistical, and economic hassles of the recent past medical researchers to study and understand the physio-

when massive cyclotrons were the only options for the logical and mental workings of the human body and the

manufacture of radioisotopes to be used in the biosyn- biology of human disease.

thesis of radiopharmaceuticals. 8

Also contributing to the advancement of PET in the

THE 1980s—PET’s aDvancEmEnTs anD

1980s were a number of radiopharmaceutical develop-

PErformancE In THE rEsEarcH sEcTor

ments, which included a report by scientists in Brookhaven National Laboratory of the high uptake of FDG in

PET remained largely a research modality into the tumors. In another development, scientists at UCLA 1980s-the decade during which the technology of PET

reported how the use of FDG showed different patterns advanced greatly. The advancement was driven by sev-

of glucose metabolism in the brain while subjects per- eral developments. One development was that of a higher

formed a variety of tasks using different senses. A third resolution PET scanner, such as the one developed by

radiopharmacetical development was the attempt of many Thomas F. Budinger (a Biological and Environmental

PET centers to determine cardiac viability, employing N- Research [BER] scientist) and colleagues in 1986. From

13 to monitor blood flow and FDG to monitor glucose an operation standpoint, the number of steps in the scan-

metabolism. The determination of cardiac viability via ning procedure of the newer PET scanners was reduced

the use of PET imaging has been considered by some as and many of the remaining steps were automated,

instrumental in the making of clinical PET into a reality. making operation of the scanner less complex. Thus, the

At the same time, others contend that the use of PET in new scanning procedures were able to be performed by

the diagnosis, management, and treatment of cancer has, trained technologists and experienced physicians (rather

since the mid1990s, contributed to increased reimburse- than by physicists and chemists), ultimately contributing

ment for PET services, which has in turn fostered PET’s to reducing the cost of the procedure.

ultimate transition from a vehicle of research to a sought-

A second development was the block detector, which after instrument in the clinical sector. contains 8 x 8 crystals multiplexed to 4 phototubes.

The decade of the 1980s is the time span in which two Invented by Ronald Nutt and Mike Casey, the block

major imaging companies (i.e., General Electric [GE] and detector has made possible the development of the high

Computer Technology Imagery [CTI]) entered into the resolution tomograph that has slowed the cost of the

PET industry and gave credence to the clinical application PET scanner [and made it more affordable to the clin-

of PET, because prior to this time-the late 1980s-most ical sector] by decreasing the number of optical detec-

PET applications had been research applications. 9-11 tors needed. Prior to the invention of the block detector, one optical detector and electronics channel was needed

THE 1990s—PET’s ProgrEssIon In THE

for each crystal element. In today’s PET systems, there

clInIcal sEcTor

are more than 100,000 elements, but thanks to block detector technology, one optical detector and electronics

The decade of the 1990s is known as the decade in channel serves 144 elements.

which the widespread use of PET progressed to and The development of a line of smaller, less expensive,

made a statement in the clinical sector. As more and more more efficient cyclotrons also contributed to the advance-

members of the medical community became acquainted ment of PET by making possible the installation of

with the utility of PET and its present and future ben- cyclotrons at more hospitals for the in-house production

efits, PET imaging became increasingly sought after and of PET radioisotopes to meet the radiopharmaceutical

available in hospitals, diagnostic clinics, mobile systems, needs of PET research and clinical service. Similarly,

and physician practices. The progression of PET to the the development of a miniaturized self-shielded, low-

clinical sector has been associated with four factors: PET energy cyclotron containing chemical synthesizers for

advancements in the 1990s, a realization of PET’s ability automated production of positron-emitting radiophar-

to identify pathophysiology, increased insurance cov- maceucticals ultimately became the base technology for

erage, and availability of PET radiophamaceuticals. the concept of PET radiopharmacies. These radiophar-

PET Advancements of the 1990s dementias like Alzheimer’s disease and movement disor- In 1990, Michael Phelps headed the formation of the

ders like Parkinson’s disease, PET is also used to evaluate Institute for Clinical PET (ICP), a non-profit organi-

heart muscle function in patients with coronary artery zation whose purpose was to bring together academia,

disease and cardiomyopathy. In the research arena, PET industry and advocacy groups to educate the public,

is being used to study drug addiction, psychiatric illness, Congress and professional groups about the value of clin-

and stroke. 18

ical PET. Whole-body PET scans were introduced in 1992-an

Increased Insurance Coverage

event that kicked off the concept of whole-body imaging Before 1995, most insurers, including Medicare, did to detect primary and metastatic disease, differentiate

not reimburse PET imaging because of the high cost of between benign and malignant tumors, and assess thera-

the procedure and because they associated the procedure peutic efficacy by being able to image all of the organs

with investigation and research. Most medical facilities, of the body in a single scan. This introduction of whole-

on the other hand, could not afford the cost of setting body scans expanded FDG’s importance as a weapon

up a PET imaging system or the ongoing operational against cancer.

expense that it required. Things began to change in In the late 1990s, a new detector material called lute-

1995 when the Health Care Financing Administration tium oxyorthosilicate (LSO) began to replace the use

(HCFA) approved coverage for Rubidium-82, a gener- of bismuth germinate oxide (BGO) in PET scanners.

ator-produced tracer used in evaluating coronary artery Although PET scientists had been using BGO in the

disease. In 1998, HCFS extended coverage to include fabrication of PET scans since the late 1970s, LSO

18 fluorodeoxyglucose (FDG) for the treatment of two quickly took over and revolutionized PET imaging sys-

types of lung cancer. In 1999, Medicare agreed to cover tems because it excelled in three fundamental detector

whole body PET imaging for lymphoma, colorectal material parameters: light output, decay time, and den-

cancer, and metastatic melanoma. In 2000, the HCFA sity. The combination of LSO’s high light output [five

expanded Medicare coverage to include the use of PET times more light output than BGO] and high density

in the treatment of six cancers: lung, colorectal, lym- [slightly higher than that of BGO] served to enhance

phoma, melanoma, head and neck, and esophageal. The sharpness and contrast and thus provide superior image

coverage in each of these cancers includes diagnosis and quality-driving the resolution PET tomography to a new

staging to assessment of therapy and recurrence of dis- limit of less then 2 mm. [It is interesting to note that

ease. For non-cancer indications, coverage includes iden- the resolution for positron tomography was 6 mm eleven

tifying and treating those cardiac patients who would years ago and 4 mm during the time of BGO detectors.]

benefit from coronary revascularization and those epi- The short decay time [LSO decays 7.5 times faster than

lepsy patients who would benefit from surgery. BGO] translated to decreased scan time-an improvement that made patients more comfortable during the proce-

Availability of the PET Radioisotope, FDG dure and from a clinical standpoint increased patient

As discussed elsewhere in this article, FDG was not throughput. The increase in patient throughput made

readily available until a few years ago because it is cyclo- the procedure accessible to greater numbers of patients

tron produced and because it has a relatively short half- and subsequently increased the testing revenue for hospi-

life of 110 minutes. Facilities wanting to offer PET tals and PET imaging centers. The short decay time also

imaging have been faced with the prohibitive costs of lowered the level of random noise in scans. 12-17

purchasing and installing a cyclotron and maintaining its operation or alternatively with finding an outside source

PET’s Ability to Identify Pathophysiology for obtaining FDG. Opportunely, PET radiopharma- As mentioned earlier in this article, PET, because it is

cies that manufacture FDG have popped up all over the based on biological substrates, is able to detect rates of

United States. By manufacturing and distributing FDG metabolic activity while other imaging modalities, such

in their regional areas, radiopharmacies have formed a as CT and MRI, depict anatomical location of struc-

continually-expanding network that has made it possible tures. From a clinical point of view, this means that

for community hospitals and outpatient clinics to offer disease can be detected by PET during times when ana-

PET services. 19-21

tomic structures are still normal. In clinical terms, this means that disease can be detected earlier rather than

THE 2000s—THE PET/cT scannEr

later, since changes in metabolic processes precede anatomical and structural changes. PET’s ability to detect

The PET/CT scanner was produced and marketed in metabolic activity has been especially applicable in the

the year 2000. Featured in Time magazine that year as field of oncology because malignancies are detected

“Invention of the Year, the PET/CT scanner was intro- earlier in the disease cycle when treatment efficacy is

duced as the fusion of a state-of-the-art PET scanner at its highest. Apart from its ability to identify patho-

and a fast, multidetector spiral CT scanner as the brain- physiology, which includes neurologic illnesses, such as

child of David Townsend, a physicist at the University of

Geneva in Switzerland, and Ronald Nutt, electrical engineer and co-founder of CTI. Working intently since the early 1990s, these two scientists developed and applied computer software that combined anatomic information from CT with the unique, functional imaging of PET into one efficient scanning device.

Earlier attempts using computer algorithms to fuse data from PET and CT images made at different times emerged with only limited success, with probable reasons being the minute changes in the patient’s posture and position that inevitably occur when images are acquired on two different systems at different times. Unlike those earlier attempts, Townsend and Nutt managed to

FIGURE 1A. Schematic of SMART Scanner

create computer software that was able to control the two different imaging systems from one computer con- sole. Based on the newly created algorithms, a prototype combined PET/CT scanner was designed and built as

a collaboration between American and German companies and tested by the University of Pittsburgh School of Medicine (UPSM).

PET/CT scanners are seen by oncologists, radiologists, researchers, and patients as an innovative boon to diagnostic medical imaging because of two main advantages. First, because of their LSO-based technologies, PET/ CT scanners are able to provide unprecedented resolution in the fused images they present of both metabolic and anatomical information-information that is particularly helpful to clinicians who interpret how chemotherapy drugs affect specific metabolic activities at precise loca- tions in the body. Second, the enhanced resolution and resultant superior image quality significantly reduce patient scan times (duration of scan times varies from 20

FIGURE 1B. Illustration showing the fused PET

or 30 minutes-half the time of a PET scan), making the

and CT scan (as well as the individual PET and CT

procedure markedly more convenient and comfortable

scans).

for the patient. Also adding to the patient’s convenience and comfort is the new design of the hybrid scanner-the diameter of the tunnel has been increased to 28 inches.

convEnTIonal DIagnosTIc

In addition to the superior image quality and patient

ImagIng ProcEDurEs

comfort that are derived from the two main advantages of PET/CT, additional benefits of include less motion

Conventional diagnostic imaging procedures evaluate artifacts and fewer problems with claustrophobia. 21-23

via radiologic images normal anatomy and physiology Although PET/CT is a relatively new innovation in clin-

as well as alterations in the biochemistry of normal tis- ical imaging, clinical experience is already showing that

sues and cells caused by disease or injury. Some radio- PET/CT images provide valuable information that can be

logic images, such as x-ray, CT scan, and spiral CT, used for early diagnosis, more accurate tumor detection

pass a beam of x-rays through the part of the body and precise localization, improved biopsy sampling, and

being examined to produce an image that reveals ana- better assessment of patient responses to chemotherapy or

tomical information. Other types of radiologic images radiation therapy. These are some of the reasons why the

are obtained by using sound waves (e.g., ultrasonog- fused image of PET/CT scanner, often referred to as the

raphy, which produces an anatomical image) or electro- SMART scanner, is being increasing viewed as a result

magnetic fields (e.g., MRI and f MRI, which produce that is greater than the sum of its parts. Figure 1A is an

anatomical and functional images, respectively). PET illustration of the SMART scanner. Figure 1B contains

and SPECT, the newest innovations in the radiologic an illustration of the fused PET/CT scan as well as illus-

imaging field, produce functional images [that reveal trations of individual PET and CT scans. 24-26

metabolic information] by recording the radioactivity of IV-administered radiopharmaceuticals that travel through the body and accumulate in organs or body systems targeted for examination.

TABLE 1. Diagnostic Imaging Procedures

Procedure

Method

Positive Points

Limitations

X-rays (electromagnetic

* Uses x-ray radiation.

* Provides anatomical X-ray

waves) penetrate body tissues *

and are used to create planar

Is painless and

image.

(two-dimensional) images of

noninvasive.

body structures on film. X-rays are taken from a

* Is painless and

* Uses x-ray radiation.

* Provides anatomical Computed Tomography and arranged by a computer * Portrays soft tissue

series of different angles

noninvasive.

image. (CT)

to show a cross-sectional

structures better than x-

(three-dimensional) view of

* Requires patient breath

ray, but contrast detail is

structures in the body.

holding.

inferior to that of MRI. * Is painless and

* Uses x-ray radiation.

noninvasive.

* Provides anatomical

* Portrays soft tissue

image.

structures better than x-

* Requires patient breath

ray, but contrast detail is

holding.

inferior to that of MRI. * Improves image resolution

and diagnostic accuracy

Spiral Computed

Conventional CT improved

due to use of enhanced

Tomography (Spiral

with dramatic scanning

contrast concentration and

CT)

speed and thinner slices.

decreased respiratory and cardiac artifacts.

* Has superior planar and three-dimensional reformation capabilities.

* Affords greater patient comfort and department productivity.

Uses a scanner to record dis-

* Is expensive to use.

tribution and accumulation

Provides images of * Radioactive chemical

of radiopharmaceuticals (i.e., natural body compounds

metabolic activity,

injected.

like glucose tagged with a

allowing study of body

* The patient is required

positron-emitting radioiso-

function.

to lie still.

Resolution of PET Positron Emission

tope) and IV-injected into

Enables early detection of *

the bloodstream.

Tomography (PET)

disease

images is lower than

A computer constructs two- * Radioactive of

that of CT or MRI.

or three-dimensional images

radiopharmaceutical is

* Can give unreliable

based on recorded informa-

low; therefore, patient

results if patient’s

tion of the distribution and

exposure to radiation is

chemical balances are

accumulation of the radio-

low.

not normal. Diabetic

pharmaceutical throughout

patients need special

the body.

consideration.

Procedure

Method

Positive Points

Limitations

Like PET, uses scanner to record distribution and concentration of the radiopharmaceuticals throughout the body.

* Is expensive to use.

Key differences between

Radioactive chemical

PET and SPECT are:

Is less expensive than PET

injected.

(PET=$2,000-$3,000;

• PET uses positron-

SPECT=$700).

emitting radiopharma-

* Image resolution is

inferior to that of PET Single Photon Emission

ceuticals (which emit

* Provides functional image

because emission of Computed Tomography

two photons) and coin-

(measures metabolism).

cidence detection that

single photon requires

(SPECT) use of collimator to

does not require a col-

SPECT’s radioisotopes

limator while SPECT

(key components of

acquire image data,

uses single-photon-emit-

radiopharmaceuticals) have

resulting in tremendous

ting radiopharmaceuticals

longer half-lives [than

decrease in detection

that require the use of

PET’s] and can be stored

efficiency.

collimator.

on site.

• SPECT radiopharmaceu-

* The patient is required

ticals directly emit pro-

to lie still.

tons while PET radiopharmaceuticals emit positrons which are converted to protons.

* No x-ray or radioactive

chemical used.

* Is expensive to use.

Uses detection of radio fre- * Is painless and quency signals produced

* Provides anatomical

noninvasive.

by displaced radio waves

image.

in a magnetic field (8,000

* Provides exquisite image

Magnetic Resonance * times stronger than that of clarity. Patient required to lie Imaging (MRI)

the earth) to create two- or

still.

* Has ability to create

three-dimensional images

detailed images without

* Claustrophobic

of body structures. Provides

contrast media. However,

patients—a problem.

anatomical or structural

use of gadolinium to

image.

image blood vessels and

* Patients with metallic

soft tissues like the brain

devices—a problem.

is growing.

Procedure

Method

Positive Points

Limitations

fMRI (functional Magnetic

Resonance Imaging)

Relies on magnetic properties of blood to produce images that portray blood flow as it is happening.

Is used to study the physiology of the brain and other organs by studying related blood flow.

No x-ray or radioactive chemical used.

Is painless; noninvasive Provides both anatomical

and functional images. Provides exquisite image

clarity [superior to PET and SPECT]. In-plane resolution of image is generally about 1.5 x 1.5 mm, although resolutions of <1 mm are possible.

Has ability to assess blood flow and brain function in seconds [in a shorter time than PET and SPECT].

Total scan time is short— on the order of 1.5 to 2.0 min per run.

Is expensive to use. Patient required to lie

still. Claustrophobic

patients—a problem. Patients with metallic

devices—a problem.

Ultrasonography

Pulsed, high frequency (>20,000 Hz) sound waves are aimed into the body, reflected back from body tissues, and processed by

a computer as a contin- uous, real-time image on a monitor.

Does not employ ionizing radiation and produces no biological injury.

Can be employed in a number of planes (e.g., transaxial, saggital, coronal, or any oblique plane) to show anatomic region being investigated.

Is far less expensive than CT, MRI, PET, or SPECT.

Can be performed portably—at bedside, for example.

Real-time ultrasound can provide moving images (e.g., the heart and fetus).

Image resolution inferior to that of CT, MRI, PET, or SPECT.

The earlier diagnostic imaging procedures of x-ray and CT scan have paved the way for the diagnostic imaging procedures of MRI, PET, and SPECT and have been perceived by many opinion leaders as harbingers of the radiology of the future. The medical professionals of today use all of these diagnostic imaging procedures to evaluate their patients’ diseases or medical conditions. The choice of which imaging procedure or procedures to use is based on the disease or medical condition being evaluated, the uniqueness of each patient’s situation, and on the procedures’ positive points and limitations. Table

1 briefly describes each diagnostic imaging procedure, lists its positive points and limitations, and serves as a vehicle of comparison of the procedures listed.

In sum, the major differences between PET and the diagnostic imaging procedures listed in Table 1 are two:

PET uses an IV-injected radiopharmaceutical to facilitate the creation of images as compared to the x-ray beams used in x-ray and CT scan, the sound waves used in ultrasonography, and the strong magnetic field used in MRI. Unlike some other radiopharmaceuticals that directly emit gamma rays, PET radiopharmaceuticals, emit positrons that are ultimately converted to gamma rays.

PET’s images visualize function, in that they portray metabolic or biochemical processes (physiology), while the other imaging procedures, such as CT and MRI, visualize structure and shape (anatomy). Unlike conventional MRI, the images of functional MRI (fMRI) portray function and provide exquisite clarity, superior to that of PET and SPECT. PET’s ability to present images that visualize function means that it can detect disease when anatomic studies are still normal-since changes in function typically precede changes in structure or anatomy. From an oncology perspective, this means that PET can differentiate benign tissue changes from malignant ones long before associated structural differences become apparent in anatomic imaging procedures. Thus, PET makes possible effective treatment in the early stages of cancer-the stages in which success of treatment is most likely. 17,26

The development of PET spans many decades and includes the contributions of many outstanding physicists, chemists, biologists, physicians, and businessmen, a number of whom have devoted their lives to the advancement of the technology. These contributions have been instrumental in transforming the non-invasive diagnostic imaging procedure from a limited medical research tool that initially employed a small number of radiation sensors and constructed images of low resolution and sensitivity to a primary, sophisticated imaging device based on a larger number of higher quality radiation sensors and improved computer programs that produces images of high resolution and sensitivity. Today’s modern PET scanners are easier to install and to operate and they offer numerous capabilities (such as speedier procedures and

movies of parts of the body) for clinicians to use as they perform imaging procedures.

In addition to these technological advances, PET has undergone a gradual but steady transition from a sophisticated research environment to the clinical sector where it is being employed in the diagnosis, treatment, and follow-up of patients in the disciplines of oncology, psy- chiatry, and neurology.

How PET works

Positron emission tomography (PET) is a nuclear medicine scanning procedure that employs the electronic detection of short-lived positron-emitting radiopharmaceuticals (substances containing a carrier molecule, such as glucose, and a positron-emitting radioactive isotope that labels or tags the carrier molecule) to study and visualize human physiology. During the PET scanning procedure, physicians and researchers are able to measure in detail the functioning of the human brain and other organs while patients remain comfortable, conscious, and alert. The PET scanner or camera generates three-dimensional images of the distribution of an IV-administered radiopharmaceutical within the body. The images enable the monitoring and evaluation of such bodily processes as glucose metabolism, oxygen metabolism, and cerebral blood f low. Ongoing indications are that PET’s monitoring and evaluation of the body’s metabolic processes have added a new dimension to the diagnosis and treatment of a variety of diseases and that the procedure will serve as a valuable tool for patients’ follow-up care.

To understand how PET works, we begin with a look at what happens during a PET scan from a physics perspective and at how the PET scanner or camera records, analyzes, and interprets those happenings. Then we look at the PET scan procedure from the patient’s perspective-what the patient sees and experiences and what happens behind the scenes. Included in that perspective are particulars on how the scan is created and how differently healthy and unhealthy tissue are portrayed on the scan. Finally, we discuss the key radiopharmaceuticals used in PET, as well as how they are made and their unique appropriateness in the clinical applications of oncology, cardiology, and neurology. In the second section, we set forth the major obstacles (i.e., equipment expense, setting up a PET system, insurance reimbursement) that have been seen by many as hindrances to the proliferation of PET as a clinical procedure. We include in the discussion measures that have been taken to combat those obstacles and the particulars of how and why those measures have made PET more accessible to more medical centers and hospitals and ultimately to more patients.

TEcHnIcal consIDEraTIons

emitting radioisotopes. The emission occurs as positrons emerge from the decaying nuclei of radioactive isotopes specifically created in cyclotrons for use in the synthesis of radiopharmaeuticals. Positrons, which are produced when radioactive substances decay, are subatomic particles that have all of the characteristics of electrons (i.e., mass, size, magnitude of charge), except polarity of charge. Positrons ([e+] positively charged) are the antimatter equivalents of electrons ([e-] negatively charged), which physicists clas- sify as matter. Like all other forms of antimatter, positrons live short, violent lives. When matter (electrons) collides with its corresponding antimatter (positrons), the electrons and positrons are destroyed and their mass is transformed into a pair of high-energy gamma rays that speed away [from the collision] in opposite directions. It is on the basis of this principle that the positrons emitted from radiopharmaceuticals during PET scan procedures are transformed into gamma rays that are detected by gamma cameras or PET scanners (Figure 2) and pro- spectively reconstructed into images. 27,28

After a radiopharmaceutical is injected intravenously

FIGURE 2. In the PET scanner above can be seen

into a patient’s bloodstream, it is distributed throughout

a collision of a positron and electron, their annihi-

the patient’s body and accumulates in the organ or body

lation , the creation of two resultant gamma rays,

system being examined where positrons [(e+) or anti-

the speeding away of the gamma rays 180 degrees

matter] are emitted and travel in the surrounding tissue

from each other, their detection by the detectors in the

dispersing kinetic energy until they encounter and collide

scanner that encircles the patient.

with one of many nearby electrons [(e-) or matter]. During the collision, the two particles combine and destroy each

Coincidence Detection other in a process that physicists refer to as annihilation. The distance that a positron travels in tissue before anni-

Unlike some other diagnostic imaging modalities hilation depends on the kinetic energy of the positron whose radiopharmaceuticals directly emit gamma rays,

when it is emitted. Usually, this distance varies from one PET uses radiopharmaceuticals that contain positron-

to two millimeters (Table 2).

TABLE 2. Positron-Emitting Radiopharmaceuticals Used in PET*

Biomedical Radiopharmaceutical

Physical

Mean

Radioisotope Half-life

Positron

Production Application

(min)

Range (mm)

Fluorodeoxyglucose (FGD)

glucose metabolism O-15 Water

blood flow; brain studies

blood flow C-11 SCH23390

N-13 Ammonia

Nitrogen-13

9.96 1.5 cyclotron

mapping serotonin and C-11 Flumazenil

Carbon-11

20.3 1.1 cyclotron

GABA receptors Rubidium

Rubidium-82

1.25 5.9 generator

myocardial perfusion studies

*This table does not contain the complete list of radiopharmaceuticals used in PET. Among the radiopharmaceuticals not included are 18-F DOPA, which is used in the treatment of Parkinson’s disease, and 11C-thymidine and 11C-methionine, which are used to study tumors of lower metabolism.

The annihilation results in a burst of electromagnetic monly used in PET scanners include bismuth germinate energy that is manifested in the discharge of two 511-keV

oxide (BGO), thallium-doped sodium iodide (NaI TI), gamma rays (according to Einstein’s famous equation:

and lutetium oxyorthosilicate (LSO). The BGO crystals,

E = mc 2 ). As shown in Figure 3, the two gamma rays are which in the recent past have generally been used in con- discharged “coincidentally” 180 degrees apart, and they

ventional PET imaging, have high spatial resolution, and travel outward in opposite directions from each other,

are 50% percent more efficient than NaI (IT) crystals. forming a coincidence line. The coincidence line, which

BGO detectors are best suited for imaging isotopes with is an indicator that annihilation has occurred somewhere

long half-lives, such as Fluorine-18 and Carbon-11. LSO along its trajectory, serves as a vital component in the

crystals offer the best combination of properties for PET detection scheme by which PET images are created.

imaging because they have a higher number of protons per atom and density when compared to BGO, which results in higher detection efficiency. 12

FIGURE 3. Illustration of the discharge of

2 gamma rays at 180 degrees from each other when a positively-charged positron collides with a negatively-charged electron.

Coincidence Imaging The two gamma rays, speeding away in opposite direc-

tions (180 degrees apart) from each other, are detected on opposite sides of the patient’s body by a PET scanner or gamma camera that surrounds the patient as he or she

FIGURE 4. View (from the top) of a patient moving

moves slowly through the scanner as shown in Figure 4.

into a PET scanner.

This sort of coincidence detection is possible because the detectors (thousands of them) are arranged in a ring configuration around the interior of the scanner, with each detector having an associate partner detector on the opposite side of the ring. In some instances, each detector consists of a scintillating crystal and a photomultipler tube. A more recent, more common configuration is the block detector, which as Figure 5 shows, consists of a rectangular bundle of crystals (referred to as a block) optically coupled to several photomultipliers. Invented by Ronald Nutt, electrical engineer and co- founder of Computer Technology Imagery, Inc. (CTI, Inc.) in the 1980s, the block detector has lowered the cost of the PET scanner by decreasing the number of optical detectors needed.

When a gamma ray is sensed by a detector, the gamma

FIGURE 5. A block detector consisting of a 7 x 8

ray activates the scintillation crystal, which converts it into

array of crystals coupled to four photomultiplier tubes.

a burst of light photons. The light photons are detected and amplifiedevent that is registered by the electronics of

The electronics of the scanner employ a time frame the scanner. The types of scintillation crystals most com-

known as a coincidence window to determine whether known as a coincidence window to determine whether

A radiopharmaceutical containing a positron- nanoseconds of each other, the detectors register an anni-

emitting radioisotope is administered intravenously into the patient’s bloodstream.

hilation/coincidence event as valid and record it. The PET scanner collects all coincident events (usu-

* The radiopharmaceutical is distributed through ally about 500,000 events) and sorts them in the form of

the body via blood circulation, accumulating in the lines into a sinogram (Figure 6), which stores informa-

organs or body systems being studied. tion in a way that is favorable for image reconstruction. The sinogram is then reconstructed with corrections by a

* The radioisotope decays, emitting positrons. computer linked to the scanner to produce a two-dimen-

A positron (e+), the antimatter equivalent of an sional image, using algorithms similar to those employed

electron, disperses most of its kinetic energy as it in computed tomography (CT), magnetic resonance

passes through the body’s tissue environment before imaging (MRI), and single photon emission computed

colliding with one of the nearby electrons (e-). tomography (SPECT). The image, which can be viewed in axial, sagittal, or coronal planes (Figure 7), depicts the

* During the collision, the positively-charged positron localization and concentration of the radiopharmaceu-

and the negatively-charged electron destroy each tical within the organ or body system that was scanned.

other and annihilation occurs. All commercially available PET scanners simultaneously

* The annihilation results in a burst of acquire data for three-dimensional images, either by

electromagnetic energy that is manifested in the imaging the entire volume as a unit or by stacking adja-

discharge of two 511-keV gamma rays 180 degrees cent two-dimensional slices. 1,4,12,19

apart, traveling outward in opposite directions along

a line that passes through the point of annihilation. * The PET scanner detects the gamma rays outside

the patient’s body. The detection of a gamma ray happens in this way.

A gamma ray is sensed by one of the scanner detectors, each of which is comprised of scintillation crystal and a photomultipler tube or alternatively as a block detector that consists of rectangular bundle of crystals optically coupled to several photomultiplers.

• When the gamma ray interacts with the scintil-

FIGURE 6. A sinogram with coincidence lines. lation crystal, its energy is converted to a burst

of light photons. • The photons are detected and amplified by the

photo-multiplier. • The photomultiplier then generates an electronic

signal and sends it to the electronics of the scanner. * The scanner electronics record the electronic signals

and determine which of the electronic signals are coincident. Coincidence is determined in this way.

• The electronics of the computer employ a time frame or coincidence window.

• Based on that time frame, if two coincident gamma rays are detected on opposite sides of the patient’s body within nanoseconds of each other, the computer pairs and records them into coincident events, forming a coincidence line.

A computer linked to the scanner reconstructs the coincident event information into images that

FIGURE 7. PET images can be viewed in axial, portray the activity of the radiopharmaceutical in coronal, or sagittal planes. the patient’s body. The image is reconstructed in

this way.

The PET scanner collects all coincident events and sorts them into a sinogram.

The sinogram is reconstructed with corrections by the computer to produce two- or three- dimensional images using algorithms similar to those employed in CT and MRI.

THE PET scan ProcEDurE

After undergoing a preliminary review of his or her medical history and a blood glucose test, the patient receives an IV-injection of a positron-emitting radiopharmaceutical that was recently synthesized from a cyclotron-manufactured, positron-emitting radioisotope. In less than an hour while the patient relaxes, the radiopharmaceutical, which is mildly radioactive, disperses throughout the body via the blood stream and accumulates in the organ or system being evaluated. The amount of radiation exposure is minimal— less, actually, than the radiation dose from many x-ray procedures. The particular radiopharmaceutical is chosen based on its affinity for a particular organ or body system. The time required for a radiopharmaceutical’s distribution and accumulation varies, depending on the radiopharmceutical.

After allowing for the appropriate time for the distribution and accumulation of the radiopharmaceutical, the PET technologist, a skilled medical professional who has received specialized education in patient care, radiation protection, radiopharmaceuticals, and nuclear medicine techniques, positions the patient comfort- ably on a narrow table called a scanning bed that moves slowly through the PET scanner or gamma camera. As the scanning bed moves, the processes of coincidence detection and coincidence imaging take place, resulting in a series of thin slices of the organ or body system being evaluated. The slices are later reconstructed into a three-dimensional image depicting the localization and concentration of the radiopharmaceutical in that organ or body system. It is imperative that the patient be made as comfortable as possible, because he or she must remain quiet without moving during the entire scanning procedure (for 30 minutes to two hours, depending on the procedure) to assure high quality images at the end of the procedure. Certain measures, such as the use of special cushions to hold the head in place or a mask with holes for the eyes, nose, and mouth that is tied to the scanning bed, may be used in instances when patients are undergoing PET scans of the head to keep the head from moving.

History and Development of PET