Hailey A Houson1, Gregory N Nkepang1, Andria F Hedrick1, Vibhudutta Awasthi2. 1. Department of Pharmaceutical Sciences, University of Oklahoma Health Science Center, 1110 N. Stonewall Avenue, Oklahoma City, OK 73117, USA. 2. Department of Pharmaceutical Sciences, University of Oklahoma Health Science Center, 1110 N. Stonewall Avenue, Oklahoma City, OK 73117, USA. Electronic address: vawasthi@ouhsc.edu.
Abstract
Positron emission tomography (PET) of myocardial infarction (MI) by infarct avid imaging has the potential to reduce the time to diagnosis and improve diagnostic accuracy. The objective of this work was to synthesize 18F-labeled glucaric acid (FGA) for PET imaging of isoproterenol-induced cardiomyopathy in a rat model. METHODS: We synthesized 18F-FGA by controlled oxidation of 18F-fluorodeoxy glucose (FDG), mediated by 4-acetamido-2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) in presence of NaBr and NaOCl in highly-buffered reaction conditions. After ascertaining preferential uptake of 18F-FGA in necrotic as compared to normal H9c2 myoblasts, the biodistribution and circulation kinetics of 18F-FGA was assessed in mice. Moreover, the potential of 18F-FGA to image myocardial damage was investigated in a rat model of isoproterenol-induced cardiomyopathy. Isoproterenol-induced myocardial injury was verified at necropsy by tissue staining and plasma cardiac troponin levels. RESULTS: Synthesis of radiochemically pure 18F-FGA was accomplished by a 5 min, one step oxidation of 18F-FDG. Reaction yield was quantitative and no side-products were detected. Biodistribution studies showed rapid elimination from the body (ke = 0.83 h-1); the major organ of 18F-FGA accumulation was kidney. In the rat model, isoproterenol-treatment resulted in significant increase in cardiac troponin. PET images showed that the hearts of isoproterenol-treated rats accumulated significant amounts of 18F-FGA, whereas healthy hearts showed negligible uptake of 18F-FGA. Target-to-nontarget contrast for 18F-FGA accumulation became significantly more pronounced in 4 h images as compared to images acquired 1 h post-injection. CONCLUSION: 18F-FGA can be easily and quantitatively synthesized from ubiquitously available 18F-FDG as a precursor. The resultant 18F-FGA has a potential to serve as an infarct-avid agent for PET imaging of MI. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: 18F-FGA/PET will complement existing perfusion imaging protocols in therapeutic decision making, determination of revascularization candidacy and success, differentiation of ischemia from necrosis in MI, discrimination of myocarditis from infarction, and surveillance of heart transplant rejection.
Positron emission tomography (PET) of myocardial infarction (MI) by infarct avid imaging has the potential to reduce the time to diagnosis and improve diagnostic accuracy. The objective of this work was to synthesize 18F-labeled glucaric acid (FGA) for PET imaging of isoproterenol-induced cardiomyopathy in a rat model. METHODS: We synthesized 18F-FGA by controlled oxidation of 18F-fluorodeoxy glucose (FDG), mediated by 4-acetamido-2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) in presence of NaBr and NaOCl in highly-buffered reaction conditions. After ascertaining preferential uptake of 18F-FGA in necrotic as compared to normal H9c2 myoblasts, the biodistribution and circulation kinetics of 18F-FGA was assessed in mice. Moreover, the potential of 18F-FGA to image myocardial damage was investigated in a rat model of isoproterenol-induced cardiomyopathy. Isoproterenol-induced myocardial injury was verified at necropsy by tissue staining and plasma cardiac troponin levels. RESULTS: Synthesis of radiochemically pure 18F-FGA was accomplished by a 5 min, one step oxidation of 18F-FDG. Reaction yield was quantitative and no side-products were detected. Biodistribution studies showed rapid elimination from the body (ke = 0.83 h-1); the major organ of 18F-FGA accumulation was kidney. In the rat model, isoproterenol-treatment resulted in significant increase in cardiac troponin. PET images showed that the hearts of isoproterenol-treated rats accumulated significant amounts of 18F-FGA, whereas healthy hearts showed negligible uptake of 18F-FGA. Target-to-nontarget contrast for 18F-FGA accumulation became significantly more pronounced in 4 h images as compared to images acquired 1 h post-injection. CONCLUSION:18F-FGA can be easily and quantitatively synthesized from ubiquitously available 18F-FDG as a precursor. The resultant 18F-FGA has a potential to serve as an infarct-avid agent for PET imaging of MI. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: 18F-FGA/PET will complement existing perfusion imaging protocols in therapeutic decision making, determination of revascularization candidacy and success, differentiation of ischemia from necrosis in MI, discrimination of myocarditis from infarction, and surveillance of heart transplant rejection.