Novel PET Imaging of Atherosclerosis with Ga-68-Labeled NOTA-Neomannosylated Human Serum Albumin

Abstract

Activated macrophages take up F-18-FDG via glucose transporters, so this compound is useful for atherosclerosis imaging by PET. However, F-18-FDG application is limited for imaging of the heart and brain, in which glucose uptake is high, and in patients with aberrant glucose metabolism. The aims of this study were to confirm that mannosylated human serum albumin (MSA) specifically binds to the mannose receptor (MR) on macrophages and to test the feasibility of Ga-68-labeled NOTA-MSA for PET imaging of atherosclerotic plaques. Methods: The peritoneal macrophages of C57/B6 mice were collected, incubated with rhodamine B isothiocyanate-MSA (10 mu g/mL), and evaluated by con focal microscopy and flow cytometry. The same evaluations were performed after preincubation of the macrophages with anti-CD206 MR blocking antibodies. NOTA-MSA was synthesized by conjugating 2-(p-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid to MSA, followed by labeling with Ga-68. Rabbits with atherosclerotic aorta induced by a 3-mo cholesterol diet and chronic inflammation underwent consecutive PET/CT with F-18-FDG and Ga-68-NOTA-MSA at 2-d intervals. Results: The binding of MSA to MR and its dose-dependent reduction by preincubation with anti, CD206 MR blocking antibody were confirmed. Rhodamine B isothiocyanate and fluorescein isothiocyanate fluorescence colocalized at the atherosclerotic plaque. The Ga-68-NOTA-MSA SUVs of the atherosclerotic aorta were significantly higher than those of the healthy arteries and inferior vena cava and were comparable to those obtained with F-18-FDG. Conclusion: These findings suggest that MR-specific Ga-68-NOTA-MSA is effective for detecting atherosclerosis in the aorta and is a promising radiopharmaceutical for imaging atherosclerosis because of the presence of M2 macrophages in atherosclerotic plaques.