Promising New ¹⁸F-Labeled Tracers for PET Myocardial Perfusion Imaging

WHY PET IS NOT USED MORE OFTEN FOR CLINICAL IMAGING

Given the advantages of PET, why is it not used more frequently for clinical myocardial perfusion imaging? One reason is cost. PET/CT scanners are more expensive than SPECT or SPECT/CT scanners, both to purchase and to maintain. Currently, clinical PET myocardial perfusion imaging is performed using either ⁸²Rb or ¹³N-NH_3. ⁸²Rb is eluted from a bedside generator, and there are periodic ongoing costs associated with generator replacement when the generator reaches the end of its service life (usually between 2 and 8 wk). Generator life is determined by its manufacturing characteristics, not its number of uses. As a result, costs per ⁸²Rb imaging procedure are reduced by maximizing the number of imaging studies performed during the useful life of the generator. ¹³N-NH₃, the other tracer used for clinical PET perfusion imaging, is cyclotron-produced and has only a 10-min half-life. If this tracer is to be used for clinical perfusion imaging, the cyclotron has to be near the imaging center. In addition, close coordination between personnel at the imaging center and personnel at the cyclotron is required to ensure that the ¹³N-NH₃ is available at the time it is needed for the stress injection.

Aside from the economic considerations, both ⁸²Rb and ¹³N-NH₃ have other limitations. ⁸²Rb is impractical for exercise stress perfusion imaging because of its short 75-s half-life. Gastrointestinal background activity may be high, even in fasting patients. Images obtained with ¹³N-NH₃ typically exhibit prominent background activity in the liver and may also show prominent pulmonary uptake in many cases. Moreover, some patients without coronary artery disease may exhibit relatively low tracer uptake in the inferolateral region of the ventricle on ¹³N-NH₃ images, possibly because of genetic differences in tracer retention (8,9).

ADVANTAGES OF AN ¹⁸F-LABELED PERFUSION TRACER

Because of the limitations of ⁸²Rb and ¹³N-NH₃, a perfusion tracer labeled with ¹⁸F for PET imaging is attractive clinically. The half-life of ¹⁸F is almost 110 min, which is long enough to permit the transport of unit doses of ¹⁸F-labeled perfusion tracers from a regional cyclotron to a PET imaging center. Therefore, either exercise or vasodilator stress myocardial perfusion imaging could be performed at centers that are presently performing only ¹⁸F-FDG PET/CT imaging for oncology patients. The extra cost of adding myocardial perfusion imaging to the case mix for such a center would likely be modest if unit doses of an ¹⁸F-labeled perfusion tracer were available at a reasonable price. If ¹⁸F-labeled perfusion tracers were available as unit doses, more PET imaging centers could perform cardiac perfusion studies. These studies could be performed with or without ¹⁸F-FDG for the assessment of myocardial viability (e.g., as part of a 2-d imaging protocol), thereby increasing the numbers of patients with access to PET myocardial imaging studies.

Because the positron emitted by ¹⁸F is relatively low-energy, travel distances in tissue before annihilation are significantly shorter than with ⁸²Rb and somewhat shorter than with ¹³N-NH₃. The result is myocardial images that are more sharply defined than those obtained with the other perfusion tracers. Moreover, as initial experience with ¹⁸F-flurpiridaz suggests, ¹⁸F-labeled tracers may offer better target-to-background ratios than the present tracers, yielding higher-quality images (10).

¹⁸F-LABELED FLUOROALKYLPHOSPHONIUM SALTS FOR PERFUSION IMAGING

In a preclinical study appearing in this issue of The Journal of Nuclear Medicine, Kim and colleagues assess the suitability of 3 ¹⁸F-labeled fluoroalkylphosphonium salts for PET myocardial perfusion imaging (11). Similar to ^99mTc-sestamibi and ^99mTc-tetrofosmin, these moieties depend on high mitochondrial membrane potentials for retention in cardiac myocytes. In the current study, (5-¹⁸F-fluoropentyl)triphenylphosphonium cation (¹⁸F-FPTP), (6-¹⁸F-fluorohexyl)triphenylphosphonium cation (¹⁸F-FHTP), and (2-(2-¹⁸F-fluoroethoxy)triphenylphosphonium cation (or ¹⁸F-FETP) were compared with ¹³N-NH₃ in Sprague–Dawley rat hearts.

In studies on isolated Langendorff perfused hearts, the authors found higher first-pass extraction fractions for all 3 ¹⁸F-labeled tracers than for ¹³N-NH₃ at flow velocities exceeding 4.0 mL/min. A higher first-pass extraction fraction indicates that net myocardial uptake of the tracer will more closely parallel tissue perfusion at high flow rates_. On perfusion images, therefore, slight differences in hyperemic flow rate should be more readily detectable than on ¹³N-NH₃ images, suggesting that PET imaging with the new perfusion tracers will prove more sensitive for detecting moderate coronary stenoses. The authors also performed dynamic PET imaging on normal rats and rats with infarctions using a small-animal PET/CT tomograph. Areas of infarction were well defined on the ¹⁸F-labeled perfusion images. Moreover, at 10 min after tracer injection, myocardium-to-liver ratios were 3–5 times higher for the ¹⁸F-labeled images than the ¹³N-NH₃ images, and myocardium-to-lung ratios were approximately 2–3 times higher. Target-to-background ratios were therefore considerably better with the newer tracers, resulting in better image quality. These preclinical studies thus indicate that the ¹⁸F-labeled phosphonium cations are promising PET myocardial perfusion tracers.

CHALLENGES AHEAD

Several major hurdles must of course be overcome to transfer the findings of a promising preclinical study into daily practice. Safety and biodistribution studies are a prerequisite to use in humans, and a well-designed hierarchy of clinical trials using appropriately constructed imaging protocols is necessary to confirm efficacy and secure Food and Drug Administration approval for clinical use. ¹⁸F-flurpiridaz, another tracer of myocardial perfusion, is in stage III clinical trials and may be the first ¹⁸F-labeled PET perfusion tracer to be approved by the Food and Drug Administration for clinical practice. Nevertheless, the new ¹⁸F-labeled fluoroalkylphosphonium tracers may also one day prove useful for human studies and could provide an additional option for clinical PET perfusion imaging. Ultimately, it is hoped that cardiac care will benefit from access of greater numbers of patients to PET myocardial perfusion imaging.

DISCLOSURE

No potential conflict of interest relevant to this article was reported.