Selective Imaging of Matrix Metalloproteinase-13 to Detect Extracellular Matrix Remodeling in Atherosclerotic Lesions

Abstract

Purpose: Overexpression and activation of matrix metalloproteinase-13 (MMP-13) within atheroma increases susceptibility to plaque rupture, a major cause of severe cardiovascular complications. In comparison to pan-MMP targeting [ 18 F]BR-351, we evaluated the potential for [ 18 F]FMBP, a selective PET radiotracer for MMP-13, to detect extracellular matrix (ECM) remodeling in vascular plaques possessing markers of inflammation.Procedures: [ 18 F]FMBP and [ 18 F]BR-351 were initially assessed in vitro by incubation with en face aortae from 8 month-old atherogenic ApoE -/mice. Ex vivo biodistributions, plasma metabolite analyses, and ex vivo autoradiography were analogously performed 30 minutes after intravenous radiotracer administration in age-matched C57Bl/6 and ApoE -/mice under baseline or homologous blocking conditions. En face aortae were subsequently stained with Oil Red O (ORO), sectioned, and subject to immunofluorescence staining for Mac-2 and MMP-13.Results: High-resolution autoradiographic image analysis demonstrated target specificity and regional concordance to lipid-rich lesions. Biodistribution studies revealed hepatobiliary excretion, low accumulation of radioactivity in non-excretory organs, and few differences between strains and conditions in non-target organs. Plasma metabolite analyses uncovered that [ 18 F]FMBP exhibited excellent in vivo stability (≥74% intact) while [ 18 F]BR-351 was extensively metabolized (≤37% intact). Ex vivo autoradiography and histology of en face aortae revealed that [ 18 F]FMBP, relative to [ 18 F]BR-351, exhibited 2.9-fold greater lesion uptake, substantial specific binding (68%), and improved sensitivity to atherosclerotic tissue (2.9-fold vs 2.1-fold). Immunofluorescent staining of aortic en face cross-sections demonstrated elevated Mac-2 and MMP-13 positive areas within atherosclerotic lesions identified by [ 18 F]FMBP ex vivo autoradiography.Conclusions: While both radiotracers successfully identified atherosclerotic plaques, [ 18 F]FMBP showed superior specificity and sensitivity for lesions possessing features of destructive plaque 3 remodeling. The detection of ECM remodeling by selective targeting of MMP-13 may enable characterization of high-risk atherosclerosis featuring elevated collagenase activity.

Identification of hub genes and regulatory networks in histologically unstable carotid atherosclerotic plaque by bioinformatics analysis

“…Through enrichment analysis of co-DEGs, we identified biological processes, cellular compartments and molecular functions associated with unstable carotid plaques. Atherosclerosis is associated with uncontrolled extracellular matrix (ECM) remodeling [ 23 ]. Reduced collagen content in ECM is a typical feature of unstable plaques [ 24 ].…”

Non-Invasive Modalities in the Assessment of Vulnerable Coronary Atherosclerotic Plaques

“…Through the use of a tracer that targets vascular cell adhesion molecule-1, in-vivo PET/CT imaging of the aorta in murine models was successful in diagnosing atherosclerotic lesions and their extent [ 90 ]. Furthermore, utilization of a selective radiotracer for MMP-13 led to superior identification of plaques with MMP-13 expression, indicative of extracellular matrix remodeling and, thus, potentially vulnerable [ 91 ]. Additionally, (68)Ga-pentixafor is known for its binding ability to the CXC-motif chemokine receptor 4 (CXCR4), which is implicated in atherosclerosis.…”

Quinazoline-2-Carboxamides as Selective PET Radiotracers for Matrix Metalloproteinase-13 Imaging in Atherosclerosis

“…Our group recently substantiated the feasibility of detecting inflammatory plaques in mouse models of atherosclerosis with an MMP-13 selective PET radiotracer ([ 18 F]FMBP) derived from the pyrimidine-dicarboxamide inhibitor class. 41 In this comparative evaluation, [ 18 F]FMBP exhibited substantially greater plaque uptake, improved sensitivity to atherosclerotic tissue, and displayed suitable specific binding relative to the aforementioned nonselective radiotracer, [ 18 F]BR-351. Nevertheless, significant challenges remain in quantifying atherosclerotic plaques noninvasively due to the retention of radioactivity in the myocardium and liver, requiring alternative MMP-13 targeted radiotracers with improved pharmacokinetics for vascular imaging.…”

“…Our group recently substantiated the feasibility of detecting inflammatory plaques in mouse models of atherosclerosis with an MMP-13 selective PET radiotracer ([ 18 F]­FMBP) derived from the pyrimidine-dicarboxamide inhibitor class . In this comparative evaluation, [ 18 F]­FMBP exhibited substantially greater plaque uptake, improved sensitivity to atherosclerotic tissue, and displayed suitable specific binding relative to the aforementioned nonselective radiotracer, [ 18 F]­BR-351.…”