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

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 [¹⁸F]BR-351, we evaluated the potential for [¹⁸F]FMBP, a selective PET radiotracer for MMP-13, to detect extracellular matrix (ECM) remodeling in vascular plaques possessing markers of inflammation.

Procedures: [¹⁸F]FMBP and [¹⁸F]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 min 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 [¹⁸F]FMBP exhibited excellent in vivo stability (≥74% intact) while [¹⁸F]BR-351 was extensively metabolized (≤37% intact). Ex vivo autoradiography and histology of en face aortae revealed that [¹⁸F]FMBP, relative to [¹⁸F]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 [¹⁸F]FMBP ex vivo autoradiography.

Conclusions: While both radiotracers successfully identified atherosclerotic plaques, [¹⁸F]FMBP showed superior specificity and sensitivity for lesions possessing features of destructive plaque remodeling. The detection of ECM remodeling by selective targeting of MMP-13 may enable characterization of high-risk atherosclerosis featuring elevated collagenase activity.