title: Imaging atherosclerotic plaque inflammation via folate receptor targeting using a novel 18F-folate radiotracer.
abstract: Folate receptor β (FR-β) is overexpressed on activated, but not resting, macrophages involved in a variety of inflammatory and autoimmune diseases. A pivotal step in atherogenesis is the subendothelial accumulation of macrophages. In nascent lesions, they coordinate the scavenging of lipids and cellular debris to define the likelihood of plaque inflammation and eventually rupture. In this study, we determined the presence of FR-β-expressing macrophages in atherosclerotic lesions by the use of a fluorine-18-labeled folate-based radiotracer. Human endarterectomized specimens were used to measure gene expression levels of FR-β and CD68. Increased FR-β and CD68 levels were found in atherosclerotic plaques compared to normal artery walls by quantitative real-time polymerase chain reaction. Western blotting and immunohistochemistry demonstrated prominent FR-β protein levels in plaques. FR-β-positive cells colocalized with activated macrophages (CD68) in plaque tissue. Carotid sections incubated with 3'-aza-2'-[18F]fluorofolic acid displayed increased accumulation in atherosclerotic plaques through in vitro autoradiography. Specific binding of the radiotracer correlated with FR-β-expressing macrophages. These results demonstrate high FR-β expression in atherosclerotic lesions of human carotid tissue correlating with CD68-positive macrophages. Areas of high 3'-aza-2'-[18F]fluorofolic acid binding within the lesions represented FR-β-expressing macrophages. Selectively targeting FR-β-positive macrophages through folate-based radiopharmaceuticals may be useful for noninvasive imaging of plaque inflammation.
authors.forename: Adrienne
authors.initials: A
authors.lastname: Müller
authors.forename: Katharina
authors.initials: K
authors.lastname: Beck
authors.forename: Zoran
authors.initials: Z
authors.lastname: Rancic
authors.forename: Cristina
authors.initials: C
authors.lastname: Müller
authors.forename: Cindy R
authors.initials: CR
authors.lastname: Fischer
authors.forename: Thomas
authors.initials: T
authors.lastname: Betzel
authors.forename: Philipp A
authors.initials: PA
authors.lastname: Kaufmann
authors.forename: Roger
authors.initials: R
authors.lastname: Schibli
authors.forename: Stefanie D
authors.initials: SD
authors.lastname: Krämer
authors.forename: Simon M
authors.initials: SM
authors.lastname: Ametamey
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001158:Arteries / Q000737:chemistry / Q000378:metabolism; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000737:chemistry* / Q000493:pharmacokinetics; D058976:Folate Receptor 2 / Q000032:analysis* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D008954:Models, Biological; D057054:Molecular Imaging / Q000379:methods*; D058226:Plaque, Atherosclerotic / Q000737:chemistry / Q000378:metabolism*; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D019788:Fluorodeoxyglucose F18; D058976:Folate Receptor 2; C067980:CD68 antigen, human; D000097382:CD68 Molecule