Molecular Imaging of Chemokine Receptor CCR2 to Quantify Monocyte Involvement after Myocardial Infarction in Mice

Ziel/Aim Myocardial infarction (MI) evokes an organized infiltration of inflammatory leukocytes, which contribute to adverse remodeling. A molecular-targeted radiotracer that is selective for pro-inflammatory monocytes as crucial contributors to remodeling, is desirable. The chemokine C-C motif receptor type 2 (CCR2) is thought to be specific for inflammatory monocytes. We employed Ga-68-DOTA-ECL1i for targeting CCR2 after acute MI in mice by positron emission tomography (PET). Methodik/Methods Accumulation of Ga-68-DOTA-ECL1i was first determined in vitro in THP1 monocytes. Then, biodistribution and tracer kinetics in organs of interest were evaluated by dynamic PET imaging in healthy C57Bl6 mice (n=8), and selective tracer accumulation in the infarct territory was measured at 3d after permanent ligation of the left coronary artery in mice (n=10). Ergebnisse/Results Ga-68-DOTA-ECL1i uptake by THP1 cells increased with higher concentrations of cells (0.2x10 6 : 0.23±0.04; 1x10 6 : 0.32±0.09; 2x10 6 : 0.60±0.06, p=0.009). In healthy mice, Ga-68-DOTA-ECL1i displayed gradual clearance from blood (% injected dose (ID)/g, 6.88±1.02 (1min) vs 2.29±0.33 (15min) vs 0.50±0.11 (60min), p<0.001), and predominant renal clearance. Heart, liver, lung signal were low in healthy mice, supporting feasibility of selective inflammation imaging in myocardial injury models. At 3d after MI, Ga-68-DOTA-ECL1i was elevated in the infarct territory compared to the anterolateral ventricle wall in age-matched healthy controls (%ID/g, 0.76±0.19 vs 0.43±0.07, p<0.001). The signal was higher in the infarct region compared to remote non-infarcted myocardium (%ID/g, 0.65±0.15, p=0.001). There was a modest elevation in blood pool signal between MI and healthy control mice (p=0.002), suggesting higher mobilization of monocytes. Schlussfolgerungen/Conclusions Ga-68-DOTA-ECL1i exhibits favorable kinetics and low background signal to isolate inflammatory monocyte and macrophage content in the damaged region after MI. Blood pool signal needs to be considered for interpretation of tissue-specific inflammation. Identification of monocyte-derived inflammation may facilitate precise image-guided intervention to modulate myeloid cell infiltration after MI. Publication History Article published online: 14 April 2022 © 2022. Thieme. All rights reserved. Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany