PET imaging of cardiomyocyte apoptosis in a rat myocardial infarction model.

Cardiomyocyte apoptosis has been observed in several cardiovascular diseases and contributes to the subsequent cardiac remodeling processes and progression to heart failure. Consequently, apoptosis imaging is helpful for noninvasively detecting the disease progression and providing treatment guidance. Here, we tested 18 F-labeled 2-(5-fluoropentyl)-2-methyl-malonic acid (18 F-ML-10) and 18 F-labeled 2-(3-fluoropropyl)-2-methyl-malonic acid (18 F-ML-8) for apoptosis imaging in rat models of myocardial infarction (MI) and compared them with 18 F-fluorodeoxyglucose (18 F-FDG). MI was induced in Sprague-Dawley rats by permanent left coronary artery ligation. Procedural success was confirmed by echocardiography and positron emission tomography (PET) imaging with 18 F-FDG. In vivo PET imaging with 18 F-ML-10 and 18 F-ML-8 was performed in the MI models at different time points after operation. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assays and immunohistochemical analyses were used to evaluate myocardial apoptosis. In vitro cell binding assays were performed to validate 18 F-ML-8 binding to apoptotic cardiomyocytes. PET imaging demonstrated high 18 F-ML-10 and 18 F-ML-8 uptake where 18 F-FDG uptake was absent. The focal accumulation of the two tracers was high on days 1 and 3 but was not notable on days 5 and 7 after surgery. The infarct-to-lung uptake ratio was 4.29 ± 0.30 for 18 F-ML-10 and 3.51 ± 0.18 for 18 F-ML-8 (n = 6, analyzed by averaging the uptake ratios on postoperative days 1 and 3, P < 0.05). The TUNEL results showed that myocardial cell apoptosis was closely related to the focal uptake of the apoptotic tracers in the infarct area. In addition, the apoptosis rates calculated from the TUNEL results were better correlated with 18 F-ML-8 uptake than with 18 F-ML-10 uptake. Ex vivo cell binding assays demonstrated that 18 F-ML-8 accumulated in apoptotic cells but not in necrotic or normal cells. PET imaging using 18 F-ML-10 or 18 F-ML-8 allows the noninvasive detection of myocardial apoptosis in the early phase. In addition, 18 F-ML-8 may be better than 18 F-ML-10 for apoptosis imaging. We propose that PET imaging with 18 F-ML-10 or 18 F-ML-8 combined with 18 F-FDG is an alternative for detecting and assessing MI.