Journal of the American College of Cardiology

2008

DOI: 10.1016/j.jacc.2008.08.048

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Molecular Imaging of Matrix Metalloproteinase in Atherosclerotic Lesions

Shinichiro Fujimoto

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et al.

Abstract: The present data show the feasibility of noninvasive detection of MMP activity in atherosclerotic plaques, and confirm that dietary modification and statin therapy reduce MMP activity.

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Matrix Remodeling By Mmp1

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Cited by 125 publications

(116 citation statements)

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“…Accordingly, in vivo imaging of MMP activation may help predict the evolution of the disease and guide therapeutic decisions. The feasibility and potential value of in vivo MMP-targeted imaging in cardiovascular pathology has been shown in preclinical studies (11)(12)(13)(14)(15)(16)(17)(18). Many of these studies have used a macrocyclic pan-MMP targeting tracer, 99m Tc-RP805, which, based on existing preclinical data, is well-positioned to serve as a lead agent for further development.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the limited hydrosolubility of RP805 precursor is a barrier to establishing uptake specificity in vivo. As such, only a few studies, mainly in vascular and valvular disease models, have attempted to demonstrate uptake specificity of this imaging agent in vivo (15,17). We sought to address these limitations by modifying the structure of the precursor, which would improve hydrophilicity and possibly blood clearance, without affecting MMP binding.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Preclinical Evaluation of RYM1, a Matrix Metalloproteinase–Targeted Tracer for Imaging Aneurysm

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et al. 2017

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Matrix metalloproteinases (MMPs) play a key role in abdominal aortic aneurysm (AAA) development. Accordingly, MMP-targeted imaging provides important information regarding vessel wall biology in the course of aneurysm development. Given the small size of the vessel wall and its proximity with blood, molecular imaging of aneurysm optimally requires highly sensitive tracers with rapid blood clearance. To this end, we developed a novel hydrosoluble zwitterionic MMP inhibitor, RYM, on the basis of which a pan-MMP tracer, RYM1, was designed. Here, we describe the development and preclinical evaluation of RYM1 in comparison with RP805, a commonly used pan-MMP tracer in murine models of aneurysm. Methods: The macrocyclic hydroxamate-based pan-MMP inhibitor coupled with 6-hydrazinonicotinamide, RYM1, was synthesized and labeled with 99m Tc. Radiochemical stability of 99m Tc-RYM1 was evaluated by radio-high-performance liquid chromatography analysis. Tracer blood kinetics and biodistribution were compared with 99m Tc-RP805 in C57BL/6J mice (n 5 10). 99m Tc-RYM1 binding to aneurysm and specificity were evaluated by quantitative autoradiography in apolipoprotein E-deficient (apoE 2/2 ) mice with CaCl 2 -induced carotid aneurysm (n 5 11). Angiotensin II-infused apoE 2/2 (n 5 16) mice were used for small-animal SPECT/CT imaging. Aortic tissue MMP activity and macrophage marker CD68 expression were assessed by zymography and reverse-transcription polymerase chain reaction. Results: RYM1 showed nanomolar range inhibition constants for several MMPs. 99m Tc-RYM1 was radiochemically stable in mouse blood for 5 h and demonstrated rapid renal clearance and lower blood levels in vivo compared with 99m Tc-RP805. 99m Tc-RYM1 binding to aneurysm and its specificity were shown by autoradiography in carotid aneurysm. Angiotensin II infusion in apoE 2/2 mice for 4 wk resulted in AAA formation in 36% (4/11) of surviving animals. In vivo 99m Tc-RYM1 small-animal SPECT/ CT images showed higher uptake of the tracer in AAA than nondilated aortae. Finally, aortic uptake of 99m Tc-RYM1 in vivo correlated with aortic MMP activity and CD68 expression. Conclusion: The newly developed pan-MMP inhibitor-based tracer 99m Tc-RYM1 displays favorable pharmacokinetics for early vascular imaging and enables specific detection of inflammation and MMP activity in aneurysm. Abdomi nal aortic aneurysm (AAA) accounts for 10,000-15,000 recorded deaths, mainly due to rupture, in the United States each year. Current clinical guidelines for surgical repair of AAA are based on aneurysm size, expansion rate, and clinical symptoms (1). However, a significant portion of AAA ruptures occurs in patients who do not meet the criteria for AAA repair, and some large AAAs may remain stable for many years. As such, new risk-stratification tools are needed to overcome the limitations of the current approach to patient selection for AAA repair. Molecular imaging targeted at the determinants of AAA expansion and rupture appears particularly promising in this regard (2). Matrix me...

“…Accordingly, in vivo imaging of MMP activation may help predict the evolution of the disease and guide therapeutic decisions. The feasibility and potential value of in vivo MMP-targeted imaging in cardiovascular pathology has been shown in preclinical studies (11)(12)(13)(14)(15)(16)(17)(18). Many of these studies have used a macrocyclic pan-MMP targeting tracer, 99m Tc-RP805, which, based on existing preclinical data, is well-positioned to serve as a lead agent for further development.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the limited hydrosolubility of RP805 precursor is a barrier to establishing uptake specificity in vivo. As such, only a few studies, mainly in vascular and valvular disease models, have attempted to demonstrate uptake specificity of this imaging agent in vivo (15,17). We sought to address these limitations by modifying the structure of the precursor, which would improve hydrophilicity and possibly blood clearance, without affecting MMP binding.…”

Section: Discussionmentioning

confidence: 99%

Preclinical Evaluation of RYM1, a Matrix Metalloproteinase–Targeted Tracer for Imaging Aneurysm

¹

,

²

,

³

et al. 2017

View full text Add to dashboard Cite

Matrix metalloproteinases (MMPs) play a key role in abdominal aortic aneurysm (AAA) development. Accordingly, MMP-targeted imaging provides important information regarding vessel wall biology in the course of aneurysm development. Given the small size of the vessel wall and its proximity with blood, molecular imaging of aneurysm optimally requires highly sensitive tracers with rapid blood clearance. To this end, we developed a novel hydrosoluble zwitterionic MMP inhibitor, RYM, on the basis of which a pan-MMP tracer, RYM1, was designed. Here, we describe the development and preclinical evaluation of RYM1 in comparison with RP805, a commonly used pan-MMP tracer in murine models of aneurysm. Methods: The macrocyclic hydroxamate-based pan-MMP inhibitor coupled with 6-hydrazinonicotinamide, RYM1, was synthesized and labeled with 99m Tc. Radiochemical stability of 99m Tc-RYM1 was evaluated by radio-high-performance liquid chromatography analysis. Tracer blood kinetics and biodistribution were compared with 99m Tc-RP805 in C57BL/6J mice (n 5 10). 99m Tc-RYM1 binding to aneurysm and specificity were evaluated by quantitative autoradiography in apolipoprotein E-deficient (apoE 2/2 ) mice with CaCl 2 -induced carotid aneurysm (n 5 11). Angiotensin II-infused apoE 2/2 (n 5 16) mice were used for small-animal SPECT/CT imaging. Aortic tissue MMP activity and macrophage marker CD68 expression were assessed by zymography and reverse-transcription polymerase chain reaction. Results: RYM1 showed nanomolar range inhibition constants for several MMPs. 99m Tc-RYM1 was radiochemically stable in mouse blood for 5 h and demonstrated rapid renal clearance and lower blood levels in vivo compared with 99m Tc-RP805. 99m Tc-RYM1 binding to aneurysm and its specificity were shown by autoradiography in carotid aneurysm. Angiotensin II infusion in apoE 2/2 mice for 4 wk resulted in AAA formation in 36% (4/11) of surviving animals. In vivo 99m Tc-RYM1 small-animal SPECT/ CT images showed higher uptake of the tracer in AAA than nondilated aortae. Finally, aortic uptake of 99m Tc-RYM1 in vivo correlated with aortic MMP activity and CD68 expression. Conclusion: The newly developed pan-MMP inhibitor-based tracer 99m Tc-RYM1 displays favorable pharmacokinetics for early vascular imaging and enables specific detection of inflammation and MMP activity in aneurysm. Abdomi nal aortic aneurysm (AAA) accounts for 10,000-15,000 recorded deaths, mainly due to rupture, in the United States each year. Current clinical guidelines for surgical repair of AAA are based on aneurysm size, expansion rate, and clinical symptoms (1). However, a significant portion of AAA ruptures occurs in patients who do not meet the criteria for AAA repair, and some large AAAs may remain stable for many years. As such, new risk-stratification tools are needed to overcome the limitations of the current approach to patient selection for AAA repair. Molecular imaging targeted at the determinants of AAA expansion and rupture appears particularly promising in this regard (2). Matrix me...

“…In the current study, an MMP targeting probe was evaluated. Besides a role in remodeling, MMP play an important role in various other cardiovascular diseases, including atherosclerosis, [23][24][25][26][27][28][29] calcific aortic valve disease, 30 aortic aneurysm formation, 31 and pulmonary inflammation. 32 Moreover, MMP also play a role in non-cardiac diseases, notably malignancy.…”

Section: See Related Article Pp 1114-1123mentioning

confidence: 99%

Playing slot to hitting the jackpot in molecular imaging: On probability of uncovering subcellular pathogenesis vs achieving clinical applicability

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2018

Journal of Nuclear Cardiology

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Myocardial infarction (MI), despite optimal reperfusion therapy, results in substantial loss of muscle tissue through apoptosis and necrosis. The repair process post MI is traditionally divided into consecutive and partly overlapping inflammation, proliferation, and maturation phases. The initial phase is characterized by infiltration of inflammatory cells removing cellular debris, and formation of new blood vessels. Matrix metalloproteinases (MMP) and other proteolytic enzymes secreted by inflammatory cells facilitate these processes. During the proliferatory phase, fibroblasts transdifferentiate into myofibroblasts and deposit collagen in the infarct area. This is mediated by a variety of growth factors, including components of a local reninangiotensin-aldosterone system. In the final phase, the newly formed scar is consolidated through cross-linking of collagen fibers and other extracellular matrix components. The extracellular matrix plays an important role in the healing process, and an imbalance between matrix deposition and degradation can lead to adverse myocardial remodeling spiraling to heart failure. Excessive collagen deposition beyond the infarct area contributes to myocardial stiffening and loss of contractile function. On the other hand, inadequate deposition of collagen or excessive collagen degradation can lead to infarct expansion, aneurysm formation, left ventricular (LV) dilation, and even cardiac rupture.MMP are a group of zinc-dependent enzymes that degrade a large variety of extracellular matrix proteins. Approximately 25 MMP have been described and classified in the functional subgroups gelatinases, collagenases, stromelysins, and membrane-type MMP. Extensive preclinical work has suggested detrimental effect of the gelatinases MMP-2 and MMP-9. Genetic knockout of MMP-9 1,2 and MMP-2 3 restricted inflammatory response and removal of necrotic tissue and collagen deposition after experimental MI; this was associated with reduction in LV dilation and incidence of of LV rupture. Moreover, knockout of endogenous tissue inhibitors of metalloproteinases (TIMP) resulted in increased hypertrophy, dilation, and cardiac dysfunction.4,5 Also, animal studies have shown that pharmacologic MMP inhibitors reduce remodeling.6,7 Therapeutic MMP inhibition has not been successfully translated to clinical efficacy.Targeting of cardiac MMP activity has been reported using optical imaging 8 and nuclear imaging [9][10][11] probes. A non-invasive SPECT imaging of MMP activity has been reported in experimental MI in mice employing Tc-99 m-labeled broad-spectrum MMP inhibitor RP805. 10 When comparing with control mice, uptake in infarct area was fivefold higher from week 1 to 3, with slight reduction over time. Interestingly, uptake was also twofold higher in remote area, suggesting that remote imaging could become feasible. In a follow-up study by the same group, the same probe was evaluated in a larger infarct model in porcine experiments.

“…MMPs have therefore been considered ideal targets for molecular imaging of vulnerable plaque. In preclinical models of atherosclerosis, 123 I-or 125 I-labeled CGS 27023A, a broad-spectrum MMP inhibitor (32), and RP-805, a 99m Tc-labeled broad-spectrum MMP-inhibiting macrocyclic compound, have been shown to bind to atherosclerotic plaque (33,34).…”

Section: Matrix Remodeling By Mmpmentioning

confidence: 99%

Molecular Imaging of Vulnerable Coronary Plaque: A Pathophysiologic Perspective

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et al. 2017

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Atherothrombotic events in coronary arteries are most often due to rupture of unstable plaque resulting in myocardial infarction. Radiolabeled molecular imaging tracers directed toward cellular targets that are unique to unstable plaque can serve as a powerful tool for identifying high-risk patients and for assessing the potential of new therapeutic approaches. Two commonly available radiopharmaceuticals-18 F-FDG and 18 F-NaF-have been used in clinical research for imaging coronary artery plaque, and ongoing clinical studies are testing whether there is an association between 18 F-NaF uptake and future atherothrombotic events. Other, less available, tracers that target macrophages, endothelial cells, and apoptotic cells have also been tested in small groups of patients. Adoption of molecular imaging of coronary plaque into clinical practice will depend on overcoming major hurdles, ultimately including evidence that the detection of unstable plaque can change patient management and improve outcomes. Cardi ovascular disease is the number one cause of death in the United States, despite numerous advances in prevention, diagnosis, and treatment (1). Nearly half these deaths are due to acute myocardial infarction, and up to 75% of myocardial infarctions are the result of an acute thrombotic event after rupture of coronary artery plaque. Rupture-prone plaques often do not cause significant obstruction (2) and are not detectable by stress imaging, the approach most commonly used to assess risk. Identification of the rupture-prone, or vulnerable, plaque could add prognostic value and thus has become a major focus in cardiovascular diagnostics. Molecular imaging with radiopharmaceuticals has the potential to play a key role in the assessment of vulnerable plaque. In this review, we will describe advances in molecular imaging in the context of the pathophysiology associated with plaque growth and vulnerability. TECHNICAL CHALLENGES IN PET IMAGING OF CORONARY PLAQUEImaging of coronary plaque with PET tracers is difficult because of the limited spatial resolution of PET, the small size of coronary plaque, and blurring caused by cardiac and respiratory motion. To partially mitigate motion of the coronary arteries, some investigators have performed enddiastolic imaging using only a part of the PET scan, but at the expense of increased image noise (3). We are exploring computational motion correction techniques that can potentially improve image quality, and we have demonstrated that these corrections can increase the target-to-background ratios of tracer uptake within coronary plaque and reduce image noise. The approach is likely to improve detection of small foci of tracer uptake within the coronary arteries (4). THE BIOLOGY OF CORONARY PLAQUEAtherosclerotic plaque develops in response to endothelial injury and entry of low-density-lipoprotein cholesterol into the intimal layer of the vessel wall. In response to this injury, monocytes are recruited into the vessel wall and differentiate into macrophages, which take up modifi...

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