Evaluation of [68Ga]Ga-DOTA-TCTP-1 for the Detection of Metalloproteinase 2/9 Expression in Mouse Atherosclerotic Plaques

A1 Journal article (refereed)


Internal Authors/Editors


Publication Details

List of Authors: Max Kiugel, Sanna Hellberg, Meeri Käkelä, Heidi Liljenbäck, Tiina Saanijoki, Xiang-Guo Li, Johanna Tuomela, Juhani Knuuti, Antti Saraste, Anne Roivainen
Publisher: MDPI
Publication year: 2018
Journal: Molecules
Volume number: 23
Issue number: 12
Number of pages: 11
ISSN: 1420-3049


Abstract

Background: The expression of matrix metalloproteinases 2/9 (MMP-2/9) has been implicated in arterial remodeling and inflammation in atherosclerosis. We evaluated a gallium-68 labeled peptide for the detection of MMP-2/9 in atherosclerotic mouse aorta. Methods: We studied sixteen low-density lipoprotein receptor deficient mice (LDLR(-/-)ApoB(100/100)) kept on a Western-type diet. Distribution of intravenously-injected MMP-2/9-targeting peptide, [Ga-68]Ga-DOTA-TCTP-1, was studied by combined positron emission tomography (PET) and contrast-enhanced computed tomography (CT). At 60 min post-injection, aortas were cut into cryosections for autoradiography analysis of tracer uptake, histology, and immunohistochemistry. Zymography was used to assess MMP-2/9 activation and pre-treatment with MMP-2/9 inhibitor to assess the specificity of tracer uptake. Results: Tracer uptake was not visible by in vivo PET/CT in the atherosclerotic aorta, but ex vivo autoradiography revealed 1.8 +/- 0.34 times higher tracer uptake in atherosclerotic plaques than in normal vessel wall (p = 0.0029). Tracer uptake in plaques correlated strongly with the quantity of Mac-3-positive macrophages (R = 0.91, p < 0.001), but weakly with MMP-9 staining (R = 0.40, p = 0.099). Zymography showed MMP-2 activation in the aorta, and pre-treatment with MMP-2/9 inhibitor decreased tracer uptake by 55% (p = 0.0020). Conclusions: The MMP-2/9-targeting [Ga-68]Ga-DOTA-TCTP-1 shows specific uptake in inflamed atherosclerotic lesions; however, a low target-to-background ratio precluded in vivo vascular imaging. Our results suggest, that the affinity of gelatinase imaging probes should be steered towards activated MMP-2, to reduce the interference of circulating enzymes on the target visualization in vivo.


Keywords

imaging, matrix metalloproteinase

Last updated on 2019-16-09 at 06:29