<p>Molecular Imaging of Inflammation in a Mouse Model of Atherosclerosis Using a Zirconium-89-Labeled Probe</p>

Abstract

Background: Beyond clinical atherosclerosis imaging of vessel stenosis and plaque morphology, early detection of inflamed atherosclerotic lesions by molecular imaging could improve risk assessment and clinical management in high-risk patients. To identify inflamed atherosclerotic lesions by molecular imaging in vivo, we studied the specificity of our radiotracer based on maleylated (Mal) human serum albumin (HSA), which targets key features of unstable atherosclerotic lesions. Materials and Methods: Mal-HSA was radiolabeled with a positron-emitting metal ion, zirconium-89 ( 89 Zr 4+ ). The targeting potential of this probe was compared with unspecific 89 Zr-HSA and 18 F-FDG in an experimental model of atherosclerosis ( Apoe–/– mice, n=22), and compared with wild-type (WT) mice (C57BL/6J, n=21) as controls. Results: PET/MRI, gamma counter measurements, and autoradiography showed the accumulation of 89 Zr-Mal-HSA in the atherosclerotic lesions of Apoe–/– mice. The maximum standardized uptake values (SUV max ) for 89 Zr-Mal-HSA at 16 and 20 weeks were 26% and 20% higher ( P < 0.05) in Apoe–/– mice than in control WT mice, whereas no difference in SUV max was observed for 18 F-FDG in the same animals. 89 Zr-Mal-HSA uptake in the aorta, as evaluated by a gamma counter 48 h postinjection, was 32% higher ( P < 0.01) for Apoe–/– mice than in WT mice, and the aorta-to-blood ratio was 8-fold higher ( P < 0.001) for 89 Zr-Mal-HSA compared with unspecific 89 Zr-HSA. HSA-based probes were mainly distributed to the liver, spleen, kidneys, bone, and lymph nodes. The phosphor imaging autoradiography (PI-ARG) results corroborated the PET and gamma counter measurements, showing higher accumulation of 89 Zr-Mal-HSA in the aortas of Apoe–/– mice than in WT mice (9.4± 1.4 vs 0.8± 0.3%; P < 0.001). Conclusion: 89 Zr radiolabeling of Mal-HSA probes resulted in detectable activity in atherosclerotic lesions in aortas of Apoe–/– mice, as demonstrated by quantitative in vivo PET/MRI. 89 Zr-Mal-HSA appears to be a promising diagnostic tool for the early identification of macrophage-rich areas of inflammation in atherosclerosis. Keywords: positron emission tomography, molecular imaging, zirconium, human serum albumin, atherosclerosis, macrophages