Comparison of 18F-Labeled Fluoroalkylphosphonium Cations with 13N-NH3 for PET Myocardial Perfusion Imaging

Despite substantial advances in the diagnosis of cardiovascular disease, there is a need for F-18-labeled myocardial perfusion agents for the diagnosis of ischemic heart disease because current PET tracers for myocardial perfusion imaging have a short half-life that limits their widespread clinical use in PET. Thus, F-18-labeled fluoroalkylphosphonium derivatives (F-18-FATPs), including (5-F-18-fluoropentyl)triphenylphosphonium cation (F-18-FPTP), (6-F-18-fluorohexyl)triphenylphosphonium cation (F-18-FHTP), and (2-(2-F-18-fluoroethoxy)ethyl)triphenylphosphonium cation (F-18-FETP), were synthesized. The myocardial extraction and image quality of the F-18-FATPs were compared with those of N-13-NH3 in rat models. Methods: The first-pass extraction fraction (EF) values of the F-18-FATPs (F-18-FPTP, F-18-FHTP, F-18-FETP) and N-13-NH3 were measured in isolated rat hearts perfused with the Langendorff method (flow velocities, 0.5, 4.0, 8.0, and 16.0 mUmin). Normal and myocardial infarction rats were imaged with small-animal PET after intravenous injection of 37 MBq of F-18-FATPs and N-13-NH3. To determine pharmacokinetics, a region of interest was drawn around the heart, and time activity curves of the F-18-FATPs and N-13-NH3 were generated to obtain the counts per pixel per second. Defect size was analyzed on the basis of polar map images of F-18-FATP5 and N-13-NH3 Results: The EF values of F-18-FATPs and N-13-NH3 were comparable at low flow velocity (0.5 mUmin), whereas at higher flows EF values of F-18-FATPs were significantly higher than those of N-13-NH3 (4.0, 8.0, and 16.0 mUmin, P < 0.05). Myocardium-to-liver ratios of F-18-FPTP, F-18-FHTP, F-18-FETP, and N-13-NH3 were 2.10 +/- 0.30, 4.36 +/- 0.20, 3.88 +/- 1.03, and 0.70 +/- 0.09, respectively, 10 min after injection, whereas myocardium-to-lung ratios were 5.00 +/- 0.25, 4.33 +/- 0.20, 7.98 +/- 1.23, and 2.26 +/- 0.14, respectively. Although F-18-FATPs and N-13-NH3 sharply delineated myocardial perfusion defects, defect size on the N-13-NH3 images was significantly smaller than on the F-18-FATP images soon after tracer injection (0-10 min, P = 0.027). Conclusion: F-18-FATPs exhibit higher EF values and more rapid clearance from the liver and lung than N-13-NH3 in normal rats, which led to excellent image quality in a rat model of coronary occlusion. Therefore, F-18-FATPs are promising new PET radiopharmaceuticals for myocardial perfusion imaging.