Will ¹⁸F flurpiridaz replace ⁸²rubidium as the most commonly used perfusion tracer for PET myocardial perfusion imaging?

Over the past two decades, there has been steadily growing interest in positron emission tomography (PET) myocardial perfusion imaging (MPI) as an alternative to single-photon emission computed tomography (SPECT) MPI for assessment of coronary artery disease (CAD). The feasibility of PET MPI has been enhanced by the availability of on-site ⁸²rubidium (⁸²Rb) generators, eliminating the need for an on-site cyclotron.

Clinical Advantages of ⁸²Rb PET MPI Compared to Conventional SPECT MPI

• 1. Lower radiation exposure for patients and laboratory personnel1

• 2. Measurement of absolute myocardial blood flow and myocardial blood flow reserve (MBFR)

• 3. Measurement of regional and global myocardial systolic function at peak-stress (rather than post-stress as is done with SPECT MPI)2

• 4. Efficient (30 minute) rest-stress imaging protocol

• 5. Robust attenuation and scatter correction with superior diagnostic accuracy.3

The low radiation exposure is a result of the very short (76 second) half-life of ⁸²Rb. Radiation exposure for laboratory personnel is also extremely low for ⁸²Rb PET MPI as the entire protocol is performed in the PET camera, and the stress laboratory personnel and nuclear technologists can monitor the procedure from a shielded control room. There is negligible residual radioactivity present after the ⁸²Rb study, which eliminates the radiation exposure to other medical personnel who are in close proximity to the patient (e.g., a sonographer who performs a transthoracic echocardiogram immediately following the PET MPI study).

The short half-life of ⁸²Rb also facilitates a rapid rest-stress imaging protocol. Equivalent ⁸²Rb doses can be administered for rest and peak-stress images (ensuring high quality for both sets of images), without the need to delay the peak-stress ⁸²Rb infusion or increase the peak-stress dose to compensate for residual resting tracer activity.

Disadvantages of ⁸²Rb as a PET Perfusion Tracer

However, the short half-life of ⁸²Rb poses challenges as well.

• 1. ⁸²Rb PET MPI is only feasible with pharmacologic stress, as there is rapid decay of ⁸²Rb activity and insufficient time to transfer the patient from a treadmill to the PET camera for post-exercise image acquisition.

• 2. The rapid decay of ⁸²Rb makes it impossible to repeat image acquisition in the event of patient motion. If severe patient motion artifact occurs on a peak-stress ⁸²Rb image, it is necessary to repeat the pharmacologic stress infusion as well as the ⁸²Rb infusion.

There are other limitations to the use of ⁸²Rb as a perfusion tracer for PET MPI.

• 1. The ⁸²Sr/⁸²Rb generator poses a large financial burden on the nuclear cardiology laboratory and limits ⁸²Rb PET MPI to laboratories with sufficient patient volume to justify the high ongoing operating costs.

• 2. Although ⁸²Rb is an analog of potassium and is actively transported via the Na⁺/K⁺ ATPase pump (like ²⁰¹thallium, a SPECT perfusion tracer with favorable myocardial uptake properties), the myocardial extraction fraction of ⁸²Rb has been reported to be lower than that of other PET perfusion tracers.4 The lower myocardial extraction fraction leads to an earlier plateau in myocardial tracer uptake during vasodilator stress and an underestimation of the blood flow disparity between normally perfused and hypoperfused myocardial regions. The clinical implication is an underestimation of the extent and severity of CAD by ⁸²Rb PET MPI.

• 3. The positrons produced by decay of ⁸²Rb are higher in energy than the positrons produced by other PET radionuclides, resulting in a longer positron range (the average distance traveled by a positron before interacting with an electron).5 The impact of the longer positron range of ⁸²Rb is poorer spatial resolution of ⁸²Rb PET images compared to images obtained using radionuclides with a shorter positron range (e.g., ¹³NH₃ and ¹⁸F).

Because of the limitations of ⁸²Rb as a PET perfusion tracer, there has been interest in developing novel perfusion tracers for PET MPI. ¹⁸F flurpiridaz is a promising ¹⁸F-labeled PET perfusion tracer in clinical development.6,7

Favorable Properties of 18F Flurpiridaz as a PET Perfusion Tracer

• 1. The longer half-life of ¹⁸F (108 minutes) permits unit dose delivery of ¹⁸F flurpiridaz from a regional cyclotron and eliminates the need for an on-site cyclotron or an on-site ⁸²Sr/⁸²Rb generator. Unit dose delivery (depending on the price per dose) might represent an important economic advantage of ¹⁸F flurpiridaz, eliminating one of the major obstacles preventing nuclear cardiology laboratories from performing PET MPI at present.

• 2. The short positron range of ¹⁸F results in superior spatial resolution and takes full advantage of the excellent intrinsic spatial resolution of PET. The superior spatial resolution of ¹⁸F flurpiridaz might improve the ability to resolve small areas of reduced myocardial perfusion and improve detection of branch vessel stenoses.

• 3. The longer half-life of ¹⁸F would facilitate the use of treadmill exercise as an alternative to pharmacologic stress for PET MPI.

• 4. In the event of severe patient motion artifact, the longer half-life of ¹⁸F would allow for repeat image acquisition without the need to repeat the tracer injection or the pharmacologic stress agent infusion.

• 5. The very high myocardial extraction fraction of ¹⁸F flurpiridaz8 might improve detection of mild to moderate (but functionally significant) coronary artery stenoses. In theory, ¹⁸F flurpiridaz should provide a more accurate assessment of the true extent and severity of CAD compared to perfusion tracers with a lower myocardial extraction fraction (e.g., ⁸²Rb).

In this issue of the Journal, Dr. Maddahi and colleagues report data regarding the safety, tolerability, biodistribution, and radiation dosimetry of ¹⁸F flurpiridaz when injected during exercise or adenosine stress in 12 normal healthy volunteers. The information is very timely as a phase 3 clinical trial of ¹⁸F flurpiridaz is soon to begin. The authors concluded that ¹⁸F flurpiridaz was well tolerated and that the radiation dosimetry was within the clinically acceptable range. The mean effective dose for ¹⁸F flurpiridaz was 0.015 mSv/MBq for exercise stress and 0.019 mSv/MBq for adenosine stress. The dosimetry for resting ¹⁸F flurpiridaz was reported previously.9

There are a few considerations regarding the applicability of the present study to patients referred for clinically indicated PET MPI.

• 1. The study population was small (12 subjects), predominantly male (10 of 12 subjects), normal body weight (BMI 20–29), healthy, and taking no medications.

  This patient population is very different from the population of patients referred for clinically indicated PET MPI. While it is understandable that young healthy volunteers are convenient subjects for a demanding and time-consuming phase 1 study, the potential impact of this healthy young study population (i.e., lower risk for adverse events) needs to be considered.

• 2. The study was limited to exercise and adenosine stress, and therefore, the biodistribution and radiation dosimetry results cannot be directly extrapolated to dipyridamole stress, regadenoson stress, dobutamine stress, or any of the vasodilator stress agents combined with low-level treadmill exercise.

• 3. The study was performed using 2D (with collimation) rather than 3D (without collimation) PET MPI. There is potential for using lower ¹⁸F flurpiridaz tracer doses with a 3D imaging protocol.

• 4. The authors were not able to provide information regarding the radiation exposure to laboratory personnel with ¹⁸F flurpiridaz compared to ⁸²Rb. Given the long half-life of ¹⁸F, there will be potential for higher radiation exposure to laboratory personnel and other medical staff in the facility. This concern needs to be addressed, and potential solutions to minimize exposure to medical staff should be explored (e.g., shielded waiting rooms might be needed for patients undergoing ¹⁸F flurpiridaz PET MPI, and 3D PET imaging protocols should be developed to reduce ¹⁸F flurpiridaz dosing).

In the end, the feasibility of exercise stress may not emerge as an important clinical advantage of ¹⁸F flurpiridaz, as measurement of peak-exercise myocardial blood flow (and MBFR) would be technically challenging and would likely require alternative blood flow quantitative methods that do not depend on initiation of imaging prior to appearance of the tracer.10 The PET MPI imaging protocols for ¹⁸F flurpiridaz will likely be less efficient than the protocols for ⁸²Rb, with proposed delays of 60 minutes and 30 minutes between the resting and peak-stress images for exercise and adenosine stress, respectively.9 Therefore, a rest-stress ¹⁸F flurpiridaz protocol duration will undoubtedly exceed the duration of a rest-stress ⁸²Rb PET MPI protocol.

When considering the advantages and disadvantages of ⁸²Rb and ¹⁸F flurpiridaz as tracers for PET MPI, there are many factors to consider, including protocol efficiency, radiation exposure to patients and laboratory personnel, diagnostic capabilities, protocol flexibility, and cost of the tracer. Will ¹⁸F flurpiridaz replace ⁸²rubidium as the most commonly used perfusion tracer for PET MPI? Only time will tell.