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PET Biomarkers for Cardiac Imaging

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PET BIOMARKERS FOR CARDIAC

IMAGING

OBJECTIVES:

On successful completion of this activity, participants should be able to do the following:

1. To compare and contrast the advantages of PET to SPECT.

2. To describe the strengths and weaknesses of 82

Rb imaging.

3. To compare the mechanism of uptake between the various PET imaging

radiopharmaceuticals.

4. To categorize the FDA approved PET radiopharmaceuticals according to indications

5. To describe the strengths and weaknesses of 13

N ammonia imaging.

6. To identify the strengths and weaknesses of 18

F FDG imaging.

7. To compare and contrast the production method for each FDA approved PET

radiopharmaceutical.

8. To compare and contrast the characteristics of current and future myocardial imaging

agents

PET BIOMARKERS FOR CARDIAC IMAGING

Over the past few decades, significant improvement has been accomplished in the morbidity and

mortality from cardiovascular disease. Major contributing factors to this success are the

advancements in therapy and diagnosis.1 Single photon emission computed tomography (SPECT)

has played an important role in providing valuable information regarding myocardial perfusion

and function. Even though cardiac SPECT imaging has been very successful, there are limitations

inherently associated with its use.1,2

Because of the several advantages PET has over SPECT

imaging, the role of nuclear cardiology in the evaluation of cardiovascular disease has undergone

further a dvancement.1 There is an increasing use of clinical PET for cardiac perfusion imaging;

however, it is still limited to certain settings having a high volume of patients.3 With PET imaging,

superior spatial and temporal resolution is obtained as well as complete quantification of regional

radiopharmaceutical uptake.1,3

Also, SPECT is hampered by artifacts arising from nonuniform

attenuation, and PET imaging provides effective nonuniform attenuation correction.2

PET metabolic imaging has proved to be extremely valuable in the evaluation of myocardial

viability.2 According to Takalkar et al, the gold standard for noninvasive evaluation of the viability



of the myocardium is considered to be a combination of myocardial perfusion and metabolic

imaging utilizing PET.1

The only cardiac PET radiopharmaceuticals that have FDA approval are rubidium-82 (82

Rb),

nitrogen-13 ammonia (13

N NH3), and fluorine-18 fluorodeoxyglucose (18

F FDG). These three agents

are reimbursable by the Center for Medicaid and Medicare Services (CMS) for clinical imaging

studies. Both 82

Rb chloride and 13

N ammonia are myocardial perfusion imaging agents while 18

F

FDG is a metabolic imaging agent.2 Refer to Table 1 for information on these approved cardiac

PET radiopharmaceuticals.

Table 1 - Cardiac PET Radiopharmaceuticals

Radiopharmaceutical Physical

Half-life4

Mean +

Range (mm)5

Half-Value

Layer

(mm Pb)4

Gamma Ray Dose

Constant

(R/mCi-r/cm)4

82Rb Chloride 75.6 sec 2.6 7.0 6.1

13N NH3 9.97 min 1.4 4.0 5.91

18F FDG 109.8 min 0.2 4.0 5.73



PET PERFUSION RADIOPHARMACEUTICALS

PET myocardial perfusion imaging can be conducted at rest and during pharmacologic or exercise

stress in the diagnosis of coronary artery disease.3,6

If the myocardial perfusion images acquired

during adequate stress are normal, this implies that there is an absence of significant coronary

artery disease (CAD). However, epicardial CAD or potentially small vessel disease is implied when

stress-induced regional myocardial perfusion abnormalities or insufficient augmentation in

perfusion are observed. Irreversible myocardial injury is suggested when impaired regional

myocardial perfusion is demonstrated during both rest and stress studies.6

RUBIDIUM-82 (8 2RB) CHLORIDE

82Rb is produced from a commercially available

82Sr-

82Rb generator supplied by Bracco Diagnostics

Inc. The parent radionuclide, 82

Sr, is loaded onto a hydrous stannic oxide column; the activity in

the column at calibration time ranges from 3330 to 5550 MBq (90 to 150 mCi).7,8

82

Sr has a

physical half-life of 25 days and decays to 82

Rb, daughter radionuclide, via electron capture. 7

Every 4 weeks the 82

Sr-82

Rb generator is replaced.2 The chemical form of the daughter

radionuclide eluted is rubidium 82

Rb chloride.7 The generator is eluted with 25 to 50 mL of

additive free 0.9% Sodium Chloride Injection USP via a computer-controlled elution pump, and it is

connected to the patient by IV tubing.2,9

According to the package insert, a single dosage of 82

Rb

chloride should not exceed 2220 MBq (60 mCi), and the dosage in a multiple injection series

should not exceed 4440 MBq (120 mCi). The rate of administration should be 50 mL/min, and the

maximum volume per infusion is 100 mL. Also, the maximum cumulative infusion volume is not to

be greater than 200 mL.9

Prior to the rubidium chloride 82

Rb eluate entering the patient, it passes through a dosimeter and

sterilizing filter. Since the half-life of 82

Rb is so short, the actual batch of 82

Rb injected does not

undergo quality control testing prior to patient administration. Though, immediately prior to the

PET study, there is a careful assessment of the generator’s elution performance to verify the

correct operation of the device, to determine the total radioactivity eluted and elution profile, and

to check for potential breakthrough of 82

Sr and 85

Sr.9,10

The content of 82

Sr must not exceed 0.02

KBq/ MBq (0.02 Ci/mCi) of 82

Rb, and the 85

Sr content must not exceed 0.2 KBq/MBq (0.2

Ci/mCi) of 82

Rb.8,9

The intravenous infusion rate of 82

Rb is 1480 – 2220 MBq (40-60 mCi) over 30

to 60 seconds. To permit blood pool clearance, there is a delay of approximately 2 minutes after

infusion before imaging commences; imaging is completed within 5 minutes. The short imaging

time is because of the rapid decay and to prevent occurrence of reconstruction artifacts.3 Since

the generator is completely replenished every 10 minutes, sequential studies can be conducted

within 10 minutes.2,3

Of all of the positron emitting radionuclides, 82

Rb is characterized by the

poorest resolution. When comparing 82

Rb to 201

Tl, the image quality of 82

Rb is superior. Also, it is

not plagued by the attenuation problems and subdiaphragmatic scatter encountered with 99m

Tc

radiopharmaceuticals.3

A significant advantage with this PET radiopharmaceutical is that it is generator produced; thus, an

on-site cyclotron is not needed to conduct 82

Rb chloride PET myocardial perfusion imaging.1 Even



though the brief physical half-life of 82

Rb challenges the PET scanners’ performance limits, it

enables the swift completion of a series of resting and stress myocardial perfusion studies. So for

routine clinical utilization, 82

Rb can be a very efficient imaging radiopharmaceutical. The

preliminary obstacle may be the fixed expense of the 82

Sr-82

Rb generator. When the number of

patient studies per day is low, the cost per patient is high. However, it is competitive with SPECT

radiopharmaceuticals when the number of studies per day is in the range of 6 to 10.2

Because of the short physical half-life of 82

Rb, pharmacologic pharmaceuticals are routinely used

for the stress segment of the 82

Rb protocols.11

There has been limited experience with exercise

testing with PET. Although supine bicycle ergometry has been successfully employed with 82

Rb

PET, it has not been adopted into clinical use. As compared to treadmill exercise, bicycle stress

does not produce as great an exercise workload.12

The short physical half-life of 82

Rb can create

logistical issues in using exercise treadmill stress. These issues include requirement for rapid

transfer of the patient from the treadmill to scanner, problem of patient movement in the

immediate post-stress imaging acquisition, and the clinical staff’s radiation exposure. Also, about

40% of patients need pharmacologic stress since they are not able to obtain an optimal level of

exercise due to physical or other limiting causes.

When you consider the population of patients that are capable of exercising, there is the problem

of the duration of exercise stress being unpredictable. This can be an obstacle for 82

Rb PET since

the time between production and injection must be brief in order to avert unnecessary

radiopharmaceutical decay.11

Chow et al reported on a study involving fifty patients who

underwent both dipyridamole and treadmill exercise 82

Rb PET myocardial perfusion imaging.

Their study concluded that treadmill exercise 82

Rb PET is feasible, that the imaging results were

similar in diagnostic content, and that the image quality was superior to dipyridamole stress.

However, for patients that are not willing or not able to tolerate pharmacologic stress, treadmill

exercise may be a reasonable alternative.12

82Rb is similar to

201Tl in that it is a monovalent cation, potassium analog, and it is extracted by the

myocardial cells from the plasma by active transport via the Na+/K

+ ATPase pump.

2,3 The

myocardial extraction of 82

Rb and 201

Tl is similar; however, 13

N ammonia has a slightly higher

extraction. The extraction of 82

Rb can be changed by factors such as hypoxia , severe acidosis, and

ischemia.2 When the coronary blood flow becomes greater, a significant quantity of

nontransported radiopharmaceutical back-diffuses from the interstitial space and is washed away

in increasing quantities nonlinearly.13

Therefore, 82

Rb uptake is a function of both blood flow and

the integrity of the myocardial cell.2 Defects in perfusion that do not change in extent and

severity between the stress and rest images are usually classified as nonreversible or fixed.

However, perfusion defects that decrease in severity or in extent, or both, between stress and rest

are considered reversible. When defects are reversible, the degree of defect reversibility has to

be provided.6 Kidney, liver, spleen, and lung uptake is also visualized with

82Rb imaging.

9

The decay of 82

Rb is 95% by positron emission (and 5% by electron capture.

14 Besides the

emission of the positron particle and annihilation photons (511 keV), it also emits two gammas,

776 keV (15% abundance) and 1395 keV (0.5% abundance). The thyroid gland receives the highest

radiation burden, 5.6 cGy/1480 MBq ( 5.6 rad/40 mCi). The kidney is next with a radiation dose of

2.8 cGy/1480 MBq (2.8 rad/40 mCi).3



Figure 1 is a SPECT study of a 57 year-old male with coronary artery disease, a history of a

myocardial infarction, congestive heart failure, and diabetes. This study demonstrated multiple

fixed defects consistent with scar. Two months later a 82

Rb chloride perfusion study (Figure 2) was

conducted because of the SPECT’s suboptimal image quality, as a result of the patient’s body

habitus, and his diabetes. PET perfusion imaging revealed clear evidence of reversibility in the

apex, septum, and anterior wall as well as the inferior wall. In the apex and infero/lateral wall,

small areas of scar were noted. Before the PET perfusion study, the patient had been advised to

retire and minimize his daily activities, due to his extensive, irreversible heart damage. After the

PET study, a catheterization procedure was performed, and it revealed that the patient had

diffuse LAD and RCA disease. A stent was placed in the LAD, and the patient was scheduled for a

RCA stent.15

This is an example of how a PET study dramatically changed the management of a

patient’s care. The value of PET myocardial perfusion imaging has been demonstrated to be

significant in the evaluation of diabetic patients, women, obese patients, and patients having

equivocal or confusing SPECT studies.2,15

Figure 115



Figure 215



NITROGEN-13 AMMONIA (1 3N NH3)

Nitrogen-13 decays by +emission 100%, has a physical half-life of 10 minutes, and is produced by

a cyclotron.3 These three different reactions are used to produce

13N:

16

O(p,)13

N,

12

C(d,n)13

N,

13C(p,n)

13N

However, the first reaction listed (16

O(p,)13

N ) is the one used most often.14

In order to use this

agent, not only is an on-site cyclotron required but also the capability for radiochemistry

synthesis.2

After intravenous administration of 13

N NH3, it undergoes rapid clearance from the circulation. In

the first minute post-injection, 85% escapes from the blood, and only 0.4% is still present after 3.3

minutes has elapsed.3 Nitrogen-13 ammonia in the blood is comprised of neutral ammonia (NH3)

in equilibrium state with its charged ammonium ion. The molecule of neutral ammonia readily

passes through plasma and cell membranes.2

Since the uncharged, lipophilic 13

N NH3 rapidly

diffuses across the capillary endothelium and myocyte’s sarcolemma, the first-pass extraction is

high (>90%).

Because of the occurrence of back-diffusion of unfixed radiopharmaceutical, there is a reduction

in the amount retained with increasing coronary blood flow. With a coronary blood flow of 1

mL/minute per gram, the average first-pass retention is 83%; however, when the flow rate

increases to 3 mL/minute per gram, the average first-pass retention is only 60%.13

Myocardial cell

localization is also the result of metabolic conversion to 13

N-glutamine via glutamine synthetase

pathway.3,16

Within the tissues, there is subsequent trapping through incorporation into the

cellular pool of amino acids. The result is that the 13

N has a relatively long biological residence

time within the heart. Besides myocardial uptake, the brain, liver, and kidneys also take up 13

N

NH3.3 It is noted that the uptake of this agent into the lungs, particularly patients having

congestive failure or are smokers, and into the liver can obstruct images; however, good to

excellent myocardial imaging can be obtained with 13

N NH3. Even in normal subjects’ hearts, there

is reduced uptake in the inferolateral myocardium due to regional heterogeneity in the uptake

and/or retention of this PET radiopharmaceutical.16

Static imaging can be performed 5 to 10 minutes after intravenously administering 370 MBq to

740 MBq (10 to 20 mCi) of 13

N NH3.1,3,16

This delay in imaging is to permit the clearance of

pulmonary and background activity. Since the myocardial biological half-life is long, this provides

some flexibility in the timing of image acquisition. In diagnosing coronary artery disease, it is

usual for a second study to be conducted after the administration of a pharmacologic stress agent,

and the protocols are similar to those utilized in SPECT myocardial perfusion imaging.3 The

physical half-life of 10 minutes makes gated acquisition possible, and it also facilitates imaging

after treadmill exercise.1



The organs receiving the highest radiation dose from 13

N NH3 are the liver and brain, with each

receiving the same dose of 0.3 cGy/740 MBq (0.3 rad/20 mCi). The heart wall, kidneys, thyroid,

ovaries, and red marrow receive 0.2 cGy/740 MBq (0.2 rad/20 mCi) each. The effective dose is 0.2

cGy/740 MBq (0.2 rad/20 mCi). In comparison to most clinically used radiopharmaceuticals, the

patient radiation absorbed dose is quite low.3

COMPARISON OF PET PERFUSION RADIOPHARMACEUTICALS

The three PET agents used in the assessment of myocardial perfusion are 82

Rb chloride, 13

N NH3,

and 15

O water; however, 15

O water does not have approval by the FDA.1,16

Oxygen-15 water has a

physical half-life of 2 minutes; like 13

N NH3, it requires an on-site cyclotron for production.10,16

Identification of coronary artery disease in patients having stenoses greater than approximately

40% is possible with the PET perfusion agents.16

The PET perfusion radiopharmaceuticals can be categorized as either freely diffusible or

extractable. Refer to Table 2. Oxygen-15 water is in the category of freely diffusible, and the

uptake and clearance of this tracer from the myocardium is based entirely on the perfusion of the

myocardium. Metabolism does not play a role. Because of these characteristics, it is considered,

theoretically, preferable to a perfusion tracer that is extracted. However, the images acquired

with diffusible tracers are inferior in quality to the extractable agents due to the fact that the

diffusible agents exist in both the blood and myocardium. This necessitates that the images be

corrected for vascular activity. Rubidium-82 chloride and 13

N NH3 are both in the category of

extractable PET radiopharmaceuticals. They distribute to the myocardium via blood flow, but

metabolic processes control their uptake and retention. Diagnostic images with these agents are

of a higher quality since the myocardium retains the extractable PET tracers and blood clearance

is usually quick. Extractable tracers can be utilized for gated functional studies since their

residence time is of sufficient length. Thus, additional diagnostic and prognostic information can

be obtained.16

Table 2 - PET Perfusion Radiopharmaceuticals



FREELY DIFFUSSIBLE EXTRACTABLE

15O water

13N NH3

82

Rb chloride

MYOCARDIAL METABOLIC RADIOPHARMACEUTICALS

Under normal fasting conditions, free fatty acids are the principal substrate for oxidative

metabolism. Under postprandial conditions the metabolic substrate changes. With a postprandial

environment resulting in increased blood glucose and therefore higher insulin levels, the heart

changes to glucose for oxidative metabolism. Along with these changes, there is also an increase

in the intracellular glycogen pool. As a result of an increased anaerobic glycolytic rate present

during ischemia and hypoxia, the myocardium uses glucose rather than free fatty acids. Under

these circumstances the utilization of exogenous glucose is not dependent on insulin. Thus, PET

imaging radiopharmaceuticals have been developed for the evaluation of myocardial glucose and

fatty acid metabolism in order to demonstrate the ischemia-induced myocardial energy substrate

use.1 The only PET metabolic radiopharmaceutical that has FDA approval for myocardial imaging

is 18

F FDG.

FLUORINE-18 FLUORODEOXYGLUCOSE (1 8F FDG)

Routinely 18

F is cyclotron produced via the18

O(p,n)18

F reaction using a target of H218

O. Commercial

suppliers sell the isotopically enriched H218

O in liquid form.14

An automated system is used in the

radiosynthesis of 18

F FDG from 18

F-fluoride ion. There are several commercially available

automated systems for this use with yields in the range of several curies of 18

F FDG.10

Fluorine-18 has a half-life of 110 minutes, and it decays 97% of the time by + emission and 3% of

the time by electron capture.14

The maximum energy of the + is 640 keV.

5 Fluorine-18 has a

resolution approaching 2 mm which is the best of all the positron emitters.3

Fluorodeoxyglucose is an analogue of glucose; a fluorine atom replaces one of the hydroxyl groups

of a glucose molecule.17

GLUT-1 and GLUT-4 transporters are responsible for transporting the FDG

into the cell comparable to glucose. Once the 18

F FDG enters the myocytes, the enzyme

hexokinase causes phosphorylation of the FDG, with the result being FDG-6-phosphate.1 This step

mirrors what happens to glucose after it enters the cell. Glucose also undergoes phosphorylation,

and it is converted into glucose-6-phosphate.13

FDG-6-phosphate does not advance through the

glycolytic pathway, pentose shunt, or glucogenesis unlike glucose-6-phosphate which continues



as a substrate for glycogen synthesis or glycolysis. 1,13

Since FDG cannot progress further, it

becomes trapped metabolically inside the myocardial cell for a extended time. By this means 18

F

FDG reveals the myocardium’s metabolic map by indicating myocardial metabolism of glucose.1,3

Even though only approximately 1% to 4% of the administered dose is trapped by the

myocardium, the target-to-background ratio is high. 18

F FDG is characterized by a multi-

compartmental blood clearance, and this clearance requires a longer time as compared to the

perfusion radiopharmaceuticals.3

The myocardial FDG uptake has been demonstrated to be heterogeneous and is dependent on the

substrate utilization by the myocardium. The choice of substrate by the myocardium is under the

influence of the hormonal environment and the concentration of the accessible substrate. Free

fatty acids are selected as the primary myocardial substrate in a setting where the plasma levels of

glucose and insulin are low but the plasma level of free fatty acids is high. However when there

are high plasma levels of glucose and insulin, glucose is the desired myocardial substrate. When

FDG PET studies are conducted on patients in a fasting condition, the myocardial uptake of FDG is

variable and often inadequate.1 The administration of glucose stimulates the secretion of insulin

with the result being an increase in the use of glucose by the myocardium.3

Different protocols are used to facilitate the optimal uptake of FDG. Glucose loading is the most

common method to promote optimal uptake of FDG, and this can be accomplished using either

oral glucose or intravenously administered dextrose.3 A characteristic protocol calls for the

patient to fast for a time period of 4 to 6 hours prior to the study. When the patient arrives, the

fasting blood sugar level is checked. If the patient is nondiabetic and the level is under 110 mg/dL,

the patient receives 25 to 100 grams of an oral glucose.1

Prior to the administration of 18

F FDG,

the blood glucose is checked to make certain that the patient is euglycemic (relating to normal

blood sugar).3

After a delay of 30 minutes to 60 minutes, 18

F FDG is intravenously administered

using a dosage of 185 – 555 MBq (5 – 15 mCi).1 Usually 60 to 90 minutes post administration of

18F FDG, images are acquired. However, if the patient is diabetic or the fasting blood sugar level

exceeds 110 mg/dL, a variation to this method is preferred in order to keep a blood level in the

range of 100 to 140 mg/dL at the time of administration of 18

F FDG. This variation also involves

the use of an oral glucose loading dose but it is supplemented with insulin.1 Diabetic patients

frequently exhibit attenuated increase in plasma insulin levels after glucose loading so there is the

requirement of small intravenous doses of insulin.3

Other protocols are also used to facilitate glucose uptake by the myocardium. Patients who have

altered gastrointestinal absorption of glucose as well as patients who do not tolerate oral glucose

can be administered dextrose intravenously.1 A protocol used principally in research settings is

the hyperinsulinemic euglycemic clamping technique.3 By administering dextrose in one arm and

insulin in the other arm, controlled metabolic conditions for the study are obtained.1,3

In order to

optimize to euglycemia, the rate is varied as needed.3 This method is hampered by being very

burdensome and hard to employ.1

Under conditions of stress, 18

F FDG may be utilized to image myocardial ischemia since the

ischemic myocardium prefers glucose over free fatty acids as its energy substrate. Glucose

loading is not needed for imaging ischemia that is exercise-induced.1



Fluorine-18 FDG delivers the greatest radiation dose to the urinary bladder wall (7.0 cGy/370 MBq

or 7 rad/10 mCi) when the bladder voiding interval is 4.8 hours. For 370 MBq (10mCi), the

effective dose equivalent is 1.1 cSv (1.1rem).17

PET MYOCARDIAL VIABILITY IMAGING

Myocardial viability is a critical consideration in the management of a patient having impaired left

ventricular function due to coronary artery disease. Perfusion imaging provides flow

measurements in these dysfunctional myocardial regions but mild to moderate flow reductions

alone are insufficient to differentiate between areas of possibly reversible dysfunction and areas

of irreversible dysfunction. However, when metabolic and perfusion PET are used together, there

is sufficient diagnostic information available to predict the functional recovery of viable

myocardium through revascularization.2

Normal myocardium demonstrates matching of perfusion and FDG uptake. Myocardial scarring is

suggested when perfusion and FDG imaging defects are matched. Severely ischemic or

hibernating myocardium is indicated when there is a photon-deficient region on perfusion imaging

but the metabolic imaging in that area demonstrates increased uptake of FDG. Myocardial

viability is indicated when there is a mismatch between perfusion imaging and FDG imaging.

After the patient with this mismatch between flow and metabolism studies undergoes

revascularization, the functional prognosis is very good. However, there is a low likelihood of

improved function post therapeutic intervention when both the perfusion and glucose

metabolism are decreased abnormally on imaging.3

CHARACTERISTICS OF CURRENT CARDIAC PET AGENTS

PET has several technical advantages over SPECT that account for improved diagnostic

performance including:

1. Routinely measured, depth-dependent attenuation correction that decreases the number

of attenuation artifacts, thereby increasing specificity.

2. High spatial and contrast resolution that allows for improved detection of small perfusion

defects, thereby increasing sensitivity.



3. High temporal resolution that allows fast dynamic imaging of tracer kinetics, which

enables absolute quantification of myocardial perfusion (mL/min/g tissue), which can

greatly enhance diagnostic sensitivity in certain patient types.

13

N NH3

82RbCl

18F FDG

Myocardial Perfusion √ √

Myocardial Tissue Viability √

High Energy √ √ √

High, Linear Uptake √ √

Absolute Blood Flow Measurement √

Short Scan Time √

Short Half-Life √ √

Pharmacologic Stress Only √ √

Long Prep Time √



A critical property of myocardial perfusion tracers is the ability of myocardial uptake to accurately

reflect changes in regional blood flow. One of the most important characteristics

is the first-pass extraction fraction parameter that describes how well a particular tracer is initially

extracted by the myocardium from the blood. The ideal tracer would be freely diffusible, with a

first-pass extraction fraction equal to unity (ie, 100% extraction), followed by very rapid blood

clearance.

The most commonly used SPECT (201Tl, 99mTc-sestamibi, and 99mTc-tetrofosmin) and PET

(82Rb) perfusion tracers have first-pass extraction fractions < 1.0 18

CHARACTERISTICS OF FUTURE CARDIAC AGENTS

New PET agents of the future will focus on heart failure, myocardial perfusion, and blood flow

measurement. Characteristics of these new PET biomarkers will help PET centers diversify their

nuclear cardiology portfolio and improve patient care. 19

A couple of examples of ideal

characteristics of myocardial perfusion imaging agents include: high cardiac uptake to non-target

ratio with minimal redistribution, improved image quality and disease detection, and an agent

that is effective with both exercise and stress. 18

CONCLUSION

Over the past few decades, significant improvement in the morbidity and mortality from

cardiovascular disease has been accomplished, but a principal cause of mortality in modern

industrialized countries is still coronary artery disease.1,2

Cardiac SPECT provides valuable data

regarding myocardial perfusion and function; however, there is a need for significant

improvement.2 The utilization of nuclear cardiology in the evaluation of cardiovascular diseases

has advanced with PET development. Improved spatial and temporal resolution and absolute

quantification of regional uptake of the radiopharmaceutical are advantages that PET has over

traditional SPECT.1 Also, the ability of PET to offer attenuation-corrected images, thus reducing

the number of artifacts along with the false-positive rate, is a significant advantage over SPECT.11

The evaluation of viability of the myocardium through the use of PET has been very useful.1

Future PET cardiac agents will continue to improve the standard of care for patients by providing

superior non-invasive imaging agents and cost-effective options to help diagnose and evaluate

cardiovascular disease. 19



REFERENCES

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119.

2. Machac J. Cardiac positron emission tomography imaging. Semin Nucl Med 2005;

35:17-36.

3. Ziessman HA, O’Malley JP, Thrall JH. Cardiac system. In: Thrall JH ed. Nuclear

Medicine: The Requisites in Radiology. 3rd

ed. Philadelphia, PA: Elsevier Mosby;

2006:450-507.

4. Kowalsky RJ, Falen SW. Radioactive decay. In: Kowalsky RJ, ed.

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ed.

Washington, D.C.: American Pharmacists Association; 2004:17-38.

5. Kowalsky RJ, Falen SW. Radiation detection and measurement. In: Kowalsky

RJ, ed. Radiopharmaceuticals in Nuclear Pharmacy and Nuclear Medicine. 2nd

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6. Schelbert HR, Beanlands R, Bengel F, et al. PET myocardial perfusion and glucose

metabolism imaging: Part 2−Guidelines for interpretation and reporting. J Nucl

Cardiol 2003; 10:557-571.

7. Kowalsky RJ, Falen SW. Radionuclide production. In: Kowalsky RJ, ed.

Radiopharmaceuticals in Nuclear Pharmacy and Nuclear Medicine. 2nd

ed.


8. Saha GB. Synthesis of PET radiopharmaceuticals. In: Basics of PET Imaging: Physics,

Chemistry, and Regulations. United States: Springer Science+Business Media, Inc.;

2005:111-124

9. CardioGen-82® [package insert]. Princeton, NJ: Bracco Diagnostics Inc.; Revised May

2000.

10. Moerlein SM. Radiopharmaceuticals for positron emission tomography. In: Kowalsky

RJ, ed. Radiopharmaceuticals in Nuclear Pharmacy and Nuclear Medicine. 2nd

ed.


11. Bateman TM. Cardiac positron emission tomography and the role of adenosine

pharmacologic stress. Am J Cardiol 2004; 94(suppl):19D-25D.

12. Chow BJW, Ananthasubramaniam K, deKemp RA, et al. Comparison of treadmill

exercise versus dipyridamole stress with myocardial perfusion imaging using

rubidium-82 positron emission tomography. J Am Coll Cardiol 2005; 45:1227-1234.

13. Kowalsky RJ, Falen SW. Heart. In: Kowalsky RJ, ed. Radiopharmaceuticals in Nuclear

Pharmacy and Nuclear Medicine. 2nd

ed. Washington, D.C.: American Pharmacists

Association; 2004:515-560.

14. Saha GB. Cyclotron and production of PET radionuclides. In: Basics of PET Imaging:

Physics, Chemistry, and Regulations. United States: Springer Science+Business Media,

Inc.; 2005:99-110.



15. PET Foundations. PET myocardial perfusion – Rubidium-82 case study (courtesy of

Dr. Michael Kipper at Pacific Imaging and Treatment Center San Diego, CA).

www.PETFoundations.com, literature number 7PET0057-01, February 2006.

16. Beller GA, Bergmann SR. Major achievements in nuclear cardiology: II: Myocardial

perfusion imaging agents: SPECT and PET. J Nucl Cardiol 2004; 11:71-86.

17. Kowalsky RJ, Falen SW. Brain. . In: Kowalsky RJ, ed. Radiopharmaceuticals in

Nuclear Pharmacy and Nuclear Medicine. 2nd

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Pharmacists Association; 2004:451-494.

18. Ming Yu, MD, PhD, *Stephen G. Nekolla, PhD, + Markus Schwaiger, MD, + and Simon

P. Robinson, PhD* The Next Generation of Cardiac Positron Emisson Tomography

Imaging Agents: Discovery of Flurpiridaz F-18 for Detection of Coronary Disease

doi:10.1053/j.semnuclmed.2011.02.004

19. Manuel Cerqueria, MD, FACC, FAHA, FASNC Beyond SPECT Perfusion: New

Radiotracers for Imaging Cardiac Sympathetic Innervation, Metabolism, and PET

Perfusion

http://www.petfoundations.com/



QUIZ

QUESTION #1

Which of the following are categorized as PET myocardial imaging agents?

○ 82Rb chloride,

13N NH3,

99mTc-tetrofosmin

○ 18F-FDG,

13N NH3,

99mTc-tetrofosmin

○ 18F-FDG,

99mTc-sestamibi

○ 82Rb chloride,

13N NH3

QUESTION #2

Which of the following are routinely provided via cyclotron production?

○ 18F

○ 82Rb

○ 18F &

13N

○ 18F,

13N, &

82Rb

QUESTION #3

Which of the following have FDA approval for myocardial perfusion imaging?

○ 18F FDG

○ 13N NH3

○ 82Rb chloride

○ 13N NH3 &

82Rb chloride



QUESTION #4

The mechanism of uptake of 82

Rb is:

○ Function of blood flow

○ Function of myocardial cell integrity

○ Function of blood flow and myocardial cell integrity

○ Related to 82

Rb being a sodium analog and blood flow

QUESTION #5

Which statement is true concerning 13

N NH3?

○ Potassium analog

○ Diffuses across capillary endothelium and myocyte’s sacrolemma

○ Charged, hydrophilic compound

○ Physical half-life of 110 minutes

QUESTION #6

Generator(s) used to produce the FDA approved PET radiopharmaceutical(s) has/have to be

replaced every:

○ Every month

○ Every 2 weeks

○ Every three months

○ Once a year



QUESTION #7

Which statement is true concerning 82

Rb chloride?

○ Each batch of 82

Rb undergoes quality control testing prior to

patient administration

○ Physical half-life of 10 minutes

○ Imaging requires 25 minutes

○ Poorest resolution of all + emitting radionuclides

QUESTION #8

Which myocardial imaging radiopharmaceutical has the best resolution of all of the FDA

approved positron emitters?

○ 18F

○ 13N

○ 82Rb

○ 15O

QUESTION #9

Which radiopharmaceutical(s) have FDA approval for metabolic imaging of the myocardium?

○ 18F FDG

○ 13N NH3

○ 82Rb chloride

○ 13N NH3 &

82Rb chloride



QUESTION #10

Which of the following statements are true concerning PET myocardial imaging?

○ Clinical PET has no advantages over SPECT

○ Clinical PET is still limited to certain settings having a high volume

of Patients

○ PET metabolic imaging has limited value in evaluating

myocardial Viability

○ SPECT is far superior to PET for myocardial blood flow evaluation

QUESTION #11

Which FDA approved PET radiopharmaceutical has the shortest

physical half-life?

○ 13N NH3

○ 18F FDG

○ 82Sr

○ 82Rb chloride

QUESTION #12

With PET myocardial imaging:

○ Normal myocardium is demonstrated by mismatch between perfusion

and metabolic imaging

○ Myocardial scarring is indicated when there is a mismatch between

perfusion and metabolic imaging

○ Hibernating myocardium is indicated when there is a photon-deficient

area on perfusion imaging with increased uptake on metabolic imaging

○ Normal myocardium is suggested when perfusion and metabolic

imaging defects are matched



QUESTION #13

Regarding substrate utilization by the myocardium:

○ Under normal fasting conditions, glucose is the principal substrate for

oxidative metabolism.

○ Principal substrate does not change between fasting and

postprandial conditions

○ Under postprandial conditions, the heart changes to free fatty acids for

oxidative metabolism.

○ During ischemia and hypoxia, there is an increase in the anaerobic

glycolytic rate.

QUESTION #14

The physical half-life of 18

F is:

○ 2 minutes

○ 20 minutes

○ 110 minutes

○ 25 days

QUESTION #15

Which of the following statement(s) is true when comparing SPECT and PET?

○ PET provides superior spatial and temporal resolution as compared

to SPECT

○ PET provides superior spatial resolution however SPECT provides

superior temporal resolution

○ In comparison to PET, SPECT has superior spatial and

temporal resolution

○ SPECT provides superior spatial resolution but PET exceeds in

temporal resolution



QUESTION #16

Which statement is true regarding 18

F?

○ Routinely prepared via generator production

○ Decays 100% of the time by + emission

○ Decays by both + emission and electron capture

○ Maximum energy of the + emission is 511 keV

QUESTION #17

In order for 82

Rb PET imaging to be competitive with SPECT in cost, the

minimum number of patient studies that have to be conducted per day is:

○ 1 to 2

○ 2 to 4

○ 4 to 5

○ 6 to 10

QUESTION #18

18F-FDG study protocol: If a patient’s fasting blood glucose is _______________, oral glucose

is still administered but it is supplemented with insulin.

○ between 70 mg/dL to 80 mg/dL



○ greater than 110 mg/dL



QUESTION #19

The organ(s) receiving the greatest radiation dose from 13

N NH3 is/are:

○ urinary bladder wall and liver

○ thyroid gland and urinary bladder wall

○ liver and brain

○ urinary bladder wall

QUESTION #20

Which statement regarding 13

N NH3 is true?

○ 13N decays by both positron emission and electron capture

○ 13N NH3 in the blood is comprised of neutral ammonia in equilibrium with its

charged ammonium ion

○ In normal subjects’ heart, there is increased uptake in the inferolateral myocardium

○ Static imaging can be performed only after a delay of 25 minutes after

intravenously administering 13

N NH3

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