PET Tracers for Clinical Cardiac Imaging Josef Machac, MD, FACC Professor of Radiology The Mount Sinai School of Medicine New York, NY

Radiotracers for Clinical Cardiac PET Imaging Myocardial perfusion/function N-13 Ammonia Cyclotron Rubidium-82 Generator Myocardial viability F-18 Fluorodeoxyglucose (FDG) The clinical PET landscape has changed dramatically over the past decade. Nearly all metropolitan areas in North America now have at least one commercial FDG supplier. A commercial rubidium-82 generator was FDA approved and commercially available at the beginning the the 90s, thus making a reliable source of racer for myocardial PET perfusion imaging, obviating the need for a cyclotron.

Radiotracers for Clinical Cardiac PET Imaging Myocardial perfusion/function N-13 Ammonia Cyclotron Rubidium-82 Generator Myocardial viability F-18 Fluorodeoxyglucose (FDG) The clinical PET landscape has changed dramatically over the past decade. Nearly all metropolitan areas in North America now have at least one commercial FDG supplier. A commercial rubidium-82 generator was FDA approved and commercially available at the beginning the the 90s, thus making a reliable source of racer for myocardial PET perfusion imaging, obviating the need for a cyclotron.

American Society of Nuclear Cardiology Injection and imaging with a myocardial imaging tracer at rest may produce decreased uptake in regions affected by myocardial infarction, or supplied by severely stenosed coronary arteries. However, most coronary artery disease will be missed if imaging is performed only at rest. American Society of Nuclear Cardiology

American Society of Nuclear Cardiology Therefore vasodilation and increased blood flow is needed to unmask most clinically significant coronary disease lesions. Vasodilation can be directly produced by intravenous adenosine and dipyridamole. Vasodilation can also be accomplished by increasing demand, through exercise or inotropic agent like dobutamine or arbutamine, which increase constractility and heart rate. Because the patient needs to be situated inside the PET scanner during the Rb-82 injection, exercise is impractical. Thus, dobutamine and arbutamine are the best second-line agents, in patients who cannot tolerate the vasodilator drugs dipyridamole and adenosine because of asthma. Either way, blood flow, and therefore tracer deposition is increased in myocardium supplied by healthy vessels, whereas blood flow is increased less in areas supplied by diseased arteries, producing relative defects. In patients with multivessel disease and the presence of collateral, blood flow can even be shunted away from the diseased regions to the more normal regions, the so called “coronary steal syndrome”. Tracer deposition is then decreased in the absolute sense. American Society of Nuclear Cardiology

Radiotracers for Clinical Cardiac PET Imaging Myocardial perfusion/function N-13 Ammonia Cyclotron Rubidium-82 Generator Myocardial viability F-18 Fluorodeoxyglucose (FDG) The clinical PET landscape has changed dramatically over the past decade. Nearly all metropolitan areas in North America now have at least one commercial FDG supplier. A commercial rubidium-82 generator was FDA approved and commercially available at the beginning the the 90s, thus making a reliable source of racer for myocardial PET perfusion imaging, obviating the need for a cyclotron.

Cardiac PET Tracers Agent Physical Mean Production Extraction half-life positron range (mm) N-13 NH3 9.9 min 0.7 cyclotron 70% Rb-82 75 sec 2.6 generator 50-60% F-18 FDG 110 min 0.2 cyclotron 1-3%

Cardiac PET Tracer Dosimetry Agent Activity TEDE Critical Organ Dose (mCi) (rem) (organ) (rem) N-13 NH3 20 0.148* Bladder 0.60** Rubidium-82 50 0.650* Thyroid 7.0** F-18 FDG 10 0.70* Bladder 5.9* * ICRP 80 ** ICRP 53

Myocardial Tracer Kinetics N-13 Ammonia 0-30s 30-60s 60-90s 90-120s 120-150s 150-180s 180-240s

N-13 Ammonia Phelps et al, 1986

Extraction of N-13 NH3 and Rb-82 Schelbert et al, Circulation 63: 1259-72, 1981 Goldstein et al, J Nucl Med 24: 907-15, 1983 Yoshida et al, J Nucl med 37: 1701-12, 1996

N-13 Ammonia UCLA School of Medicine

N-13 Ammonia Advantages Disadvantages Good quality images 10 min half-life Short positron travel Good blood flow quantification capability Can be used with pharmacological stress or exercise Disadvantages Need for on-site cyclotron production Ties up cyclotron and manpower Difficult logistics Production-Imaging 10min half-life Need for Decay between rest and stress doses (20/20mCi) Differential doses (10/30mCi)

Radiotracers for Clinical Cardiac PET Imaging Myocardial perfusion/function N-13 Ammonia Cyclotron Rubidium-82 Generator Myocardial viability F-18 Fluorodeoxyglucose (FDG) The clinical PET landscape has changed dramatically over the past decade. Nearly all metropolitan areas in North America now have at least one commercial FDG supplier. A commercial rubidium-82 generator was FDA approved and commercially available at the beginning the the 90s, thus making a reliable source of racer for myocardial PET perfusion imaging, obviating the need for a cyclotron.

Cardiac PET Tracers Agent Physical Mean Production Extraction half-life positron range (mm) N-13 NH3 9.9 min 0.7 cyclotron 70% Rb-82 75 sec 2.6 generator 50-60% F-18 FDG 110 min 0.2 cyclotron 1-3%

Cardiac PET Tracer Dosimetry Agent Activity TEDE Critical Organ Dose (mCi) (rem) (organ) (rem) N-13 NH3 20 0.148* Bladder 0.60** Rubidium-82 50 0.650* Thyroid 7.0** F-18 FDG 10 0.70* Bladder 5.9* * ICRP 80 ** ICRP 53

Rubidium-82 Generator Courtesy of Bracco Diagnostics

Rubidium-82 Generator Courtesy of Bracco Diagnostics

Mount Sinai Clinical PET Center

Cardiac Rubidium-82 Kinetics The Mount Sinai School of Medicine

The Mount Sinai School of Medicine An 8 frame, 8 minute dynamic acquisition is made. The serial images are corrected for isotope decay. Myocardial and blood pool time activity curves are generated. The Mount Sinai School of Medicine

Clinical Case-KC Stress Rest Stress Rest Stress Rest Stress Rest The stress images show LV cavity dilatation, and decreased perfusion everywhere except for the anterior basal segment. The resting images appeared normal. This is consistent with severe extensive ischemia. Rest Stress Rest Mount Sinai School of Medicine

Rubidium-82 Advantages Disadvantages Short half-life Always available Challenge to: PET cameras Staff Relatively long positron travel Need for heavier filtering More difficult quantification Fixed cost of generator Low volume Advantages Always available No need for cyclotron Efficient acquisition logistics Short half-life Can be repeated multiple times If technical difficulties Multiple stress interventions Fixed cost of generator High volume

Maximizing Obtained Dose from a Rb-82 Generator* Because of the 75 sec half-life of Rb-82, obtaining maximum activity from the generator is important. Images may suffer from noise at the end of generator lifespan. We investigated conditions predicting maximal Rb-82 activity, at various points of generator age, compared to fixed conditions and to maximal activity (PredMax) predicted from Sr-82 decay. Kim, Machac, Almeida, Clin Nucl Med 29: 135P, 2004

Obtainable Rb-82 Activity Condition A : Fixed Settings Value Day1 D7 D13 D19 D24 Dial Activity 60 60 60 60 60 Dial Volume 50 50 50 50 50 Effective Act 52.9 49 42 38.8 31.7 Pred Activity 62.6 53 44.9 38.0 33.1 El Vol 22 31 49 50 50 ElTime 26 36 58 57 58 Kim, Machac, Almeida, Clin Nucl Med 29: 135P, 2004

Obtainable Rb-82 Activity Condition B: Variable Settings Value Day1 D7 D13 D19 D24 Dial Activity 70 70 60 70 50 Dial Volume 50 50 60 50 50 Effective Act 62.6 49.3 42.1 43.4 31.7 Pred Activity 62.6 53.0 44.9 38.0 33.1 Elution Vol 22 49 49 50 50 Elution Time 37 58 58 57 55 Kim, Machac, Almeida, Clin Nucl Med 29: 135P, 2004

Kim, Machac, Almeida, Clin Nucl Med 29: 135P, 2004

Conclusions: Maximizing Obtained Dose from a Rb-82 Generator Maximal Effective Activity could be augmented only in the first week by increasing Dialed Activity. Increasing Dial Volume usually diminished Effective Activity. Effective Activity generally followed Predicted Maximum based on Sr-82 decay. Elution Time reached a plateau after Day7-Day13. Overall, optimizing Effective Activity has only marginal benefit after first week of generator life. Kim, Machac, Almeida, Clin Nucl Med 29: 135P, 2004

Quantification of Myocardial Perfusion Compartmental Models Clinically available PET imaging tracers N-13 ammonia for centers with cyclotron Rb-82 generator for centers without cyclotron

Radiotracers for Clinical Cardiac PET Imaging Myocardial perfusion/function Rubidium-82 Generator N-13 Ammonia Cyclotron Myocardial viability F-18 Fluorodeoxyglucose (FDG) The clinical PET landscape has changed dramatically over the past decade. Nearly all metropolitan areas in North America now have at least one commercial FDG supplier. A commercial rubidium-82 generator was FDA approved and commercially available at the beginning the the 90s, thus making a reliable source of racer for myocardial PET perfusion imaging, obviating the need for a cyclotron.

Cardiac PET Tracers Agent Physical Mean Production Extraction half-life positron range (mm) N-13 NH3 9.9 min 0.7 cyclotron 70% Rb-82 75 sec 2.6 generator 50-60% F-18 FDG 110 min 0.2 cyclotron 1-3%

Cardiac PET Tracer Dosimetry Agent Activity TEDE Critical Organ Dose (mCi) (rem) (organ) (rem) N-13 NH3 20 0.148* Bladder 0.60** Rubidium-82 50 0.650* Thyroid 7.0** F-18 FDG 10 0.70* Bladder 5.9* * ICRP 80 ** ICRP 53

F-18 FDG Kinetics Mount Sinai School of Medicine

F-18 FDG Kinetics The Mount Sinai School of Medicine

Myocardial FDG Uptake During Fasting The Mount Sinai School of Medicine

Myocardial FDG Uptake after Glucose Loading The Mount Sinai School of Medicine

PET Viability Imaging Rest perfusion imaging (Rb-82, N-13 ammonia, Tl-201, MIBI, Tetrofosmin) Stress perfusion imaging (if possible) Glucose management Injection of F-18 FDG Wait 60 minutes Gated FDG imaging The imaging protocol starts with overnight fasting. The patient undergoes resting perfusion imaging with Rb-82 as with the normal perfusion protocol. Whenever possible, we try to perform pharmacological stress Rb-82 perfusion imaging, in order to unmask stress-induced ischemia. On the same day or a separate day, this is followed by FDG PET imaging. This begins with glucose management. Numerous protocols have been published, using either oral or IV glucose loading, along with subcutaneous or IV insulin. We use IV glucose loading followed by IV insulin. The patient is then injected with FDG intravenously. The patient rests for 1 hour. The patient then undergoes gated PET imaging, followed by a trasmission scan.

Gated FDG PET Imaging Clicking on any of the image panels activates the cine display.

Standardization of Myocardial F-18 FDG Uptake Oral glucose loading IV bolus glucose loading Euglycemic-Hyperinsulinemic Clamp Niacin (Nicotinic Acid Derivative) Guidelines for patient preparation and data acquisition: J Nucl Cardiol 10: 543-54, 2003

* check blood glucose prior to deoxyglucose injection, Oral Glucose Loading Blood Glucose One Hour Before 18F-deoxyglucose administration < 110 mg/dl Give 50 to 100g Glucose orally * 110 to 126 mg/dl No Glucose > 126 mg/dl about 4 to 6 IU Regular Short-Acting Insulin IV. Repeat blood glucose after 15 min for > 15% decrease; If not, repeat Insulin IV * check blood glucose prior to deoxyglucose injection, if very high, insulin UCLA School of Medicine

Rb-82 and F-18 FDG images in a diabetic patient The Mount Sinai School of Medicine

The Mount Sinai School of Medicine

Substrate Utilization of Normal and of Dysfunctional Myocytes Free Fatty Acid Glucose Lactic Acid Free Fatty Acid Glucose Lactic Acid Normally Contracting Myocyte Reversibly Dysfunctional Myocyte UCLA School of Medicine

Clinical Case: JR (PET rest Rb-FDG) The Mount Sinai School of Medicine

Can Rubidium-82 Kinetics Be Used for Myocardial Viability?

Rb-82 Kinetics and Viability Gould et al. J Nucl Med 31: 1-9, 1990

Resting Rb-82 Washout Normal Mild-Mod Severe M RMM MM FDG ns P=0.007 P=0.05 Resting Rb-82 Washout This graph shows the resting Rb washout rate within each of the categories. In general, there was nearly complete overlap of washout values between the FDG match and mismatch groups within each Rb defect type, despite minimal differences between means. There was a marginally greater washout for FDG-Rb mismatch in the Mild-Moderate Rb defect category. There was no significant effect of FDG-Rb match or mismatch on resting Rb washout rate in the severe defect category. Normal Mild-Mod Severe Rest Rb-82 Almeida et al. J Nucl Med 44: P7, 2003

Rb-82 Kinetics and Viability The Mount Sinai School of Medicine

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