Amyloid-Targeting PET Tracer [18F]Flutemetamol Accumulates in Atherosclerotic Plaques.

Sanna Hellberg,Max Kiugel,Sohvi Hörkkö,Ella Hirani,Anne Roivainen,Harri Hakovirta,Pekka Saukko,Heidi Liljenbäck,Seppo Ylä-Herttuala,Veronique Morisson-Iveson,Olli Eskola,Juhani Knuuti,Antti Saraste,Johanna Silvola

doi:10.3390/molecules24061072

Abstract

Atherosclerosis is characterized by the accumulation of oxidized lipids in the artery wall, which triggers an inflammatory response. Oxidized low-density lipoprotein (ox-LDL) presents amyloid-like structural properties, and different amyloid species have recently been recognized in atherosclerotic plaques. Therefore, we studied the uptake of the amyloid imaging agent [18F]Flutemetamol in atherosclerotic plaques. The binding of [18F]Flutemetamol to human carotid artery plaque was studied in vitro. In vivo uptake of the tracer was studied in hypercholesterolemic IGF-II/LDLR−/−ApoB100/100 mice and C57BL/6N controls. Tracer biodistribution was studied in vivo with PET/CT, and ex vivo by gamma counter and digital ex vivo autoradiography. The presence of amyloid, ox-LDL, and macrophages in the plaques was examined by immunohistochemistry. [18F]Flutemetamol showed specific accumulation in human carotid plaque, especially in areas positive for amyloid beta. The aortas of IGF-II/LDLR−/−ApoB100/100 mice showed large thioflavin-S-positive atherosclerotic plaques containing ox-LDL and macrophages. Autoradiography revealed 1.7-fold higher uptake in the plaques than in a lesion-free vessel wall, but no difference in aortic tissue uptake between mouse strains were observed in the in vivo PET/CT. In conclusion, [18F]Flutemetamol binds to amyloid-positive areas in human atherosclerotic plaques. Further studies are warranted to clarify the uptake mechanisms, and the potential of the tracer for in vivo imaging of atherosclerosis in patients.

Highlights

Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipids in vessel walls, especially oxidized low-density lipoproteins, with these triggering an inflammatory response [1]
Recent studies show that higher concentrations of soluble amyloid precursor protein (APP) and Aβ in the bloodstream are associated with higher cardiovascular risk [7,8], in addition to serum amyloid A [9]
We studied the binding of [18 F]Flutemetamol to human atherosclerotic plaque sections in vitro, while the in vivo and ex vivo biodistribution of [18 F]Flutemetamol was studied in atherosclerotic and healthy mice, with more detailed uptake in the aorta being analyzed by digital autoradiography

Summary

Introduction

Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipids in vessel walls, especially oxidized low-density lipoproteins (ox-LDL), with these triggering an inflammatory response [1]. While they first appear as distinct diseases, the pathologies of atherosclerosis and Alzheimer’s disease (AD) have similarities [2,3]. Recent studies show that higher concentrations of soluble APP and Aβ in the bloodstream are associated with higher cardiovascular risk [7,8], in addition to serum amyloid A [9]. Transgenic APOE−/− mice overexpressing APP show atherosclerotic lesions of increased size and with enhanced inflammation in comparison with

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