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Aluminum fluoride-18 labeled folate enables in vivo detection of atherosclerotic plaque inflammation by positron emission tomography.

ABSTRACT: Inflammation plays an important role in the development of atherosclerosis and its complications. Because the folate receptor ? (FR-?) is selectively expressed on macrophages, an FR targeted imaging agent could be useful for assessment of atherosclerotic inflammation. We investigated aluminum fluoride-18-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid conjugated folate (¹⁸F-FOL) for the detection of atherosclerotic plaque inflammation. We studied atherosclerotic plaques in mice, rabbits, and human tissue samples using ¹⁸F-FOL positron emission tomography/computed tomography (PET/CT). Compound 2-deoxy-2-[¹⁸F]fluoro-D-glucose (¹⁸F-FDG) was used as a comparison. Firstly, we found that the in vitro binding of ¹⁸F-FOL co-localized with FR-?-positive macrophages in carotid endarterectomy samples from patients with recent ischemic symptoms. We then demonstrated specific accumulation of intravenously administered ¹⁸F-FOL in atherosclerotic plaques in mice and rabbits using PET/CT. We noticed that the ¹⁸F-FOL uptake correlated with the density of macrophages in plaques and provided a target-to-background ratio as high as ¹⁸F-FDG, but with considerably lower myocardial uptake. Thus, ¹⁸F-FOL PET/CT targeting of FR-?-positive macrophages presents a promising new tool for the in vivo imaging of atherosclerotic inflammation.

SUBMITTER: Silvola JMU

PROVIDER: S-EPMC6018703 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Aluminum fluoride-18 labeled folate enables in vivo detection of atherosclerotic plaque inflammation by positron emission tomography.

Silvola Johanna M U JMU Li Xiang-Guo XG Virta Jenni J Marjamäki Päivi P Liljenbäck Heidi H Hytönen Jarkko P JP Tarkia Miikka M Saunavaara Virva V Hurme Saija S Palani Senthil S Hakovirta Harri H Ylä-Herttuala Seppo S Saukko Pekka P Chen Qingshou Q Low Philip S PS Knuuti Juhani J Saraste Antti A Roivainen Anne A

Scientific reports 20180626 1

Inflammation plays an important role in the development of atherosclerosis and its complications. Because the folate receptor β (FR-β) is selectively expressed on macrophages, an FR targeted imaging agent could be useful for assessment of atherosclerotic inflammation. We investigated aluminum fluoride-18-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid conjugated folate (<sup>18</sup>F-FOL) for the detection of atherosclerotic plaque inflammation. We studied atherosclerotic plaques in mice, ...[more]

PMID: 29946129

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Project description:BackgroundMicrocalcifications in atherosclerotic plaques are destabilizing, predict adverse cardiovascular events, and are associated with increased morbidity and mortality.18F-fluoride positron emission tomography (PET)/computed tomography (CT) imaging has demonstrated promise as a useful clinical diagnostic tool in identifying high-risk plaques; however, there is confusion as to the underlying mechanism of signal amplification seen in PET-positive, CT-negative image regions. This study tested the hypothesis that 18F-fluoride PET/CT can identify early microcalcifications.Methods18F-fluoride signal amplification derived from microcalcifications was validated against near-infrared fluorescence molecular imaging and histology using an in vitro 3-dimensional hydrogel collagen platform, ex vivo human specimens, and a mouse model of atherosclerosis.ResultsMicrocalcification size correlated inversely with collagen concentration. The 18F-fluoride ligand bound to microcalcifications formed by calcifying vascular smooth muscle cell derived extracellular vesicles in the in vitro 3-dimensional collagen system and exhibited an increasing signal with an increase in collagen concentration (0.25 mg/mL collagen -33.8×102±12.4×102 counts per minute; 0.5 mg/mL collagen -67.7×102±37.4×102 counts per minute; P=0.0014), suggesting amplification of the PET signal by smaller microcalcifications. We further incubated human atherosclerotic endarterectomy specimens with clinically relevant concentrations of 18F-fluoride. The 18F-fluoride ligand labeled microcalcifications in PET-positive, CT-negative regions of explanted human specimens as evidenced by 18F-fluoride PET/CT imaging, near-infrared fluorescence, and histological analysis. Additionally, the 18F-fluoride ligand identified micro and macrocalcifications in atherosclerotic aortas obtained from low-density lipoprotein receptor-deficient mice.ConclusionsOur results suggest that 18F-fluoride PET signal in PET-positive, CT-negative regions of human atherosclerotic plaques is the result of developing microcalcifications, and high surface area in regions of small microcalcifications may amplify PET signal.

Dataset Information

Aluminum fluoride-18 labeled folate enables in vivo detection of atherosclerotic plaque inflammation by positron emission tomography.

Publications

Aluminum fluoride-18 labeled folate enables in vivo detection of atherosclerotic plaque inflammation by positron emission tomography.

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