Al 18 F-NOTA-folate Accumulates in Atherosclerotic Plaques and Can Be Detected by PET/CT

Introduction:Macrophages are a major cell type in inflamed atherosclerotic plaques. Since folate receptor β (FR-β) is highly expressed in activated macrophages, we hypothesized that it might serve as a new marker for inflamed atherosclerotic plaques. Hypothesis: We aimed at evaluating a FR-β targeted PET tracer, Al 18 F NOTA-Folate, for the detection of inflamed atherosclerotic plaques. Methods:Atherosclerotic mice deficient for low density lipoprotein receptor (LDLR -/- ApoB 100/100 , n=12), C57BL control mice (n=9), and Watanabe rabbits (n=4) with endothelial denudation-induced atherosclerosis in the aorta were used. Biodistribution of Al 18 F-NOTA-Folate (specific radioactivity 130 GMq/μmol) was investigated in vivo by PET/contrast enhanced CT and ex vivo by gamma counting and autoradiography of aortic sections. In addition, prior to Al 18 F-NOTA-Folate study, the Watanabe rabbits were PET/CT imaged with 18 F-FDG. Results:Atherosclerotic mice demonstrated large and macrophage-rich atheromatous plaques in the aorta. The in vivo PET/CT revealed significantly higher uptake of Al 18 F-NOTA-Folate in the aortic arch of atherosclerotic mice compared to controls (aorta-to-blood ratio 1.5±0.3 vs. 0.7±0.2, P <0.0001), which were verified by ex vivo measurements. Autoradiography confirmed focally increased uptake of Al 18 F-NOTA-Folate in the atherosclerotic plaques (plaque-to-normal vessel wall ratio 2.6±0.7, P <0.0001). Competitive study with excess of unlabelled folate reduced Al 18 F-NOTA-Folate uptake in the aorta by app. 80% and thus verified the specificity of its binding. In the rabbit aorta, the PET/CT showed a strong focal in vivo uptake of Al 18 F-NOTA-Folate co-localizing with an atherosclerotic abdominal aorta with highest aorta-to-blood ratio of 6.0. For comparison, with 18 F-FDG the ratio was 2.4 in the same area. Conclusions: Al 18 F-NOTA-Folate, targeting FR-β, accumulates in macrophage-rich atherosclerotic plaques, which can be detected in vivo by PET/CT in experimental models of atherosclerosis. Further development of the tracer for imaging of patients with atherosclerosis is warranted.