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-/-ApoB100/100) kept on a Western-type diet. Distribution of intravenously-injected MMP-2/9-targeting peptide, [68Ga]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 [68Ga]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.
Highlights
Atherosclerosis remains the leading cause of death in developed countries
The purpose of this study is to explore the feasibility of a previously-described positron emission tomography (PET) imaging probe for the assessment of matrix metalloproteinases 2/9 (MMP-2/9) expression in mouse atherosclerotic plaques
Myocardial uptake of [68 Ga]Ga-DOTA-TCTP-1 remained low in atherosclerotic uptake of [ Ga]Ga-DOTA-TCTP-1 remained low in atherosclerotic mice (0.23 ± 0.083 %ID/g) and mice (0.23 ± 0.083 %ID/g) and controls (0.16 ± 0.066 %ID/g, p = 0.54)
Summary
Atherosclerosis remains the leading cause of death in developed countries. Rupture of an atherosclerotic plaque often precedes complications of atherosclerosis, such as myocardial infarctionMolecules 2018, 23, 3168; doi:10.3390/molecules23123168 www.mdpi.com/journal/moleculesMolecules 2018, 23, 3168 or stroke. Targeted molecular imaging approaches have been tested for inflammation detection in atherosclerotic plaques, including [18 F]FDG (a marker of glucose consumption by activated macrophages) [2]. [18 F]FDG has been shown to characterize inflammation in atherosclerosis, more specific targets have been identified, such as the activation of matrix metalloproteinases in the vascular wall [3]. Peptide-based probes designed to detect specific target molecules can be conjugated with metal chelators. They have the advantage of easy and fast radiolabeling with a generator-produced radionuclide, excluding the necessity of an on-site cyclotron. The expression of matrix metalloproteinases 2/9 (MMP-2/9) has been implicated in arterial remodeling and inflammation in atherosclerosis.
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