Exploring macrophage mannose receptor expression after myocardial infarction by Al[18F]F-NOTA-DCM positron emission tomography

Abstract Introduction Mannose receptor (CD206) is primarily expressed on the surface of alternatively activated macrophages that are involved in resolution of inflammation after myocardial injury [1]. The purpose of this study was to evaluate mannose receptor targeting positron emission tomography (PET) tracer Al[18F]F-NOTA-DCM consisting of dextran backbone with cysteine-mannose moieties for imaging of experimental acute myocardial infarction (MI) [2]. Methods First, ALEXA-488 fluorophore-labelled DCM was used for specificity studies using flow cytometry of M1 and M2 polarized macrophages derived from human blood monocytes. Secondly, Sprague-Dawley rats were studied on day 3 and day 7 after permanent ligation of left coronary artery or after sham-operation. [18F]FDG PET (35 MBq, 10 min static scan) was performed to visualize myocardium and on the next day, 60 min dynamic PET was performed after injection of 50 MBq of Al[18F]F-NOTA-DCM. Then, rats were euthanized for biodistribution study by gamma counting followed by digital autoradiography and histology (H&E, CD206 staining) of left ventricle cryosections. In vitro Al[18F]F-NOTA-DCM blocking study was performed on left ventricle cryosection with molar excess of unlabelled DCM. Results Flow cytometry confirmed that ALEXA-488-DCM bound specifically to M2 macrophages. In rats, the infarcted area was clearly detected in vivo with Al[18F]F-NOTA-DCM PET and its SUV was significantly higher than that of remote area or myocardium of sham-operated rats both on day 3 (SUV 0.78±0.18 vs. 0.47±0.13 vs. 0.43±0.07, p<0.005) and day 7 post-MI (SUV 0.64±0.10 vs. 0.47±0.12 vs. 0.51±0.07, p<0.05). Autoradiography confirmed increased uptake in the infarcted area compared to the remote area or to the myocardium of sham-operated rats on day 3 (PSL/mm2 141.21±46.06 vs. 49.76±20.37 vs. 57.97±6.77, p<0.005) and day 7 (PSL/mm2 139.22±19.44 vs. 55.38±28.83 vs. 60.83±7.63, p<0.0001). In vitro blocking study indicated that the tracer binding in infarcted area was specific. The area-% of CD206-positive staining in the infarcted area was significantly higher on day 3 post-MI than on day 7 (p<0.05), and higher at both time points than in remote area or myocardium of sham-operated rats (p<0.0001). Area-% of CD206 staining in the MI area positively correlated with Al[18F]F-NOTA-DCM uptake and MI size (p<0.05 and p<0.01, respectively). Conclusions Al[18F]F-NOTA-DCM PET detects overexpression of mannose receptor after ischemic myocardial injury and may be a suitable biomarker for early detection of the inflammation resolution process after MI. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Jane and Aatos Erkko FoundationSigrid Juselius FoundationFInnish Foundation for Cardiovascular Research