Novel molecular imaging ligands targeting matrix metalloproteinases 2 and 9 for imaging of unstable atherosclerotic plaques

Molecular imaging of matrix metalloproteinases (MMPs) may allow detection of atherosclerotic lesions vulnerable to rupture. In this study, we develop a novel radiolabelled compound that can target gelatinase MMP subtypes (MMP2/9) with high selectivity and inhibitory potency. Inhibitory potencies of several halogenated analogues of MMP subtype-selective inhibitors (N-benzenesulfonyliminodiacetyl monohydroxamates and N-halophenoxy-benzenesulfonyl iminodiacetyl monohydroxamates) were in the nanomolar range for MMP2/9. The analogue with highest inhibitory potency and selectivity was radiolabelled with [123I], resulting in moderate radiochemical yield, and high radiochemical purity. Biodistribution studies in mice, revealed stabilization in blood 1 hour after intravenous bolus injection. Intravenous infusion of the radioligand and subsequent autoradiography of excised aortas showed tracer uptake in atheroprone mice. Distribution of the radioligand showed co-localization with MMP2/9 immunohistochemical staining. In conclusion, we have developed a novel selective radiolabeled MMP2/9 inhibitor, suitable for single photon emission computed tomography (SPECT) imaging that effectively targets atherosclerotic lesions in mice.

[1]  M. Sadeghi,et al.  Molecular Imaging of Angiogenesis and Vascular Remodeling in Cardiovascular Pathology , 2016, Journal of clinical medicine.

[2]  C. Supuran,et al.  Carbonic anhydrase and matrix metalloproteinase inhibitors: sulfonylated amino acid hydroxamates with MMP inhibitory properties act as efficient inhibitors of CA isozymes I, II, and IV, and N-hydroxysulfonamides inhibit both these zinc enzymes. , 2000, Journal of medicinal chemistry.

[3]  R. Ross,et al.  ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. , 1994, Arteriosclerosis and thrombosis : a journal of vascular biology.

[4]  N. Narula,et al.  Molecular Imaging of Matrix Metalloproteinase Expression in Atherosclerotic Plaques of Mice Deficient in Apolipoprotein E or Low-Density-Lipoprotein Receptor , 2009, Journal of Nuclear Medicine.

[5]  A. Newby.  Metalloproteinases promote plaque rupture and myocardial infarction: A persuasive concept waiting for clinical translation. , 2015, Matrix biology : journal of the International Society for Matrix Biology.

[6]  E. Oviedo-Orta,et al.  Comparison of MMP‐2 and MMP‐9 secretion from T helper 0, 1 and 2 lymphocytes alone and in coculture with macrophages , 2008, Immunology.

[7]  E. Boerwinkle,et al.  From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I. , 2003, Circulation.

[8]  Aloke V. Finn,et al.  Atherosclerotic Plaque Progression and Vulnerability to Rupture: Angiogenesis as a Source of Intraplaque Hemorrhage , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[9]  Kenneth M. Murphy,et al.  Functional diversity of helper T lymphocytes , 1996, Nature.

[10]  Ralph Weissleder,et al.  Molecular imaging of cardiovascular disease. , 2007, Circulation.

[11]  Peter Libby,et al.  The immune response in atherosclerosis: a double-edged sword , 2006, Nature Reviews Immunology.

[12]  T. Tuccinardi,et al.  Design, synthesis and molecular modeling study of iminodiacetyl monohydroxamic acid derivatives as MMP inhibitors. , 2006, Bioorganic & medicinal chemistry.

[13]  B. Fingleton,et al.  Matrix Metalloproteinase Inhibitors and Cancer—Trials and Tribulations , 2002, Science.

[14]  D. Wilson,et al.  Discovery of CGS 27023A, a non-peptidic, potent, and orally active stromelysin inhibitor that blocks cartilage degradation in rabbits. , 1997, Journal of medicinal chemistry.

[15]  J. Booij,et al.  In vitro and ex vivo storage phosphor imaging of short-living radioisotopes , 2008, Journal of Neuroscience Methods.

[16]  P. Shah,et al.  Inflammation and Plaque Vulnerability , 2009, Cardiovascular Drugs and Therapy.

[17]  Sanjiv S Gambhir,et al.  A molecular imaging primer: modalities, imaging agents, and applications. , 2012, Physiological reviews.

[18]  A. Jeng,et al.  Sulfonamide-based hydroxamic acids as potent inhibitors of mouse macrophage metalloelastase. , 1998, Bioorganic & medicinal chemistry letters.

[19]  Gillian Murphy,et al.  Structure and function of matrix metalloproteinases and TIMPs. , 2006, Cardiovascular research.

[20]  A. van Waarde,et al.  Probes for non-invasive matrix metalloproteinase-targeted imaging with PET and SPECT. , 2013, Current pharmaceutical design.

[21]  Otmar Schober,et al.  A new class of highly potent matrix metalloproteinase inhibitors based on triazole-substituted hydroxamates: (radio)synthesis and in vitro and first in vivo evaluation. , 2012, Journal of medicinal chemistry.

[22]  Divya Singh,et al.  Multifaceted role of matrix metalloproteinases (MMPs) , 2015, Front. Mol. Biosci..

[23]  Ingebrigt Sylte,et al.  Regulation of matrix metalloproteinase activity in health and disease , 2011, The FEBS journal.

[24]  M. Lepage,et al.  A comprehensive review on controls in molecular imaging: lessons from MMP-2 imaging. , 2014, Contrast media & molecular imaging.