Use of Novel PET Agent F-18-labeled Glucaric Acid to Image Isoproterenol-Induced Myocardial Injury

Objectives: Myocardial infarction (MI) is a leading cause of death worldwide. Clinical diagnosis of MI depends on initial electrocardiogram, levels of circulating biomarkers, and imaging of myocardial perfusion by single photon emission computed tomography (SPECT). Positron emission tomography (PET) is an alternative imaging modality, and as compared to SPECT has increased resolution, sensitivity, lower radioactive dose, and reduced imaging times. Infarct-avid agents are able to directly accumulate in the evolving necrotic infarct. There are several infarct avid agents available for SPECT imaging, but there is an unmet need for infarct avid agents for PET imaging.

Methods: ¹⁸F-labeled 2-deoxy-2-fluoro glucaric acid (FGA) was synthesized as an infarct imaging agent from commercially available ¹⁸F-FDG. Biodistribution and circulation kinetics were assessed in healthy mice. Cardiomyopathy was induced in Sprague Dawley rats by injecting high dose isoproteronol (100 mg/kg, i.p.) on two consecutive days. ¹⁸F-FGA/PET was performed before and after isoproteronol administration. ¹⁸F-FGA (1 mCi, 0.2-0.4 mL) was injected via the tail vein and the images were acquired 1, 2 and 4 h post-injection. The images were analyzed by drawing region of interest (ROI) around the heart to calculate SUV. Isoproteronol-induced myocardial injury was verified at necropsy by tissue staining with tetrazolium chloride (TTC) and plasma cardiac troponin.

Results: Synthesis of radiochemically pure ¹⁸F-FGA was accomplished by a 5 minute, one step reaction of ¹⁸F-precursor in highly-buffered reaction conditions. Biodistribution studies in healthy mice showed rapid elimination from the body (k_e = 0.83 h^-1); the major organ of ¹⁸F-FGA accumulation was the kidney. In the rat model, ISO-treatment resulted in a significant increase in cardiac troponin levels. The hearts of ISO-treated rats accumulated significant amounts of ¹⁸F-FGA, however there was negligible uptake in healthy hearts. Target-to-nontarget contrast for ¹⁸F-FGA accumulation became significantly more pronounced in 4 h images as compared to 1 h images post-injection.

Conclusion: Based on the results, we conclude that ¹⁸F-FGA effectively localizes in isoproteronol-induced cardiomyopathy and has a potential to serve as an infarct-avid agent for localizing MI by PET.