Overactivity of the brain renin-angiotensin system (RAS) has been implicated in the development and maintenance of hypertension in several experimental models, such as spontaneously hypertensive rats and transgenic mice expressing both human renin and human angiotensinogen transgenes. We recently reported that, in the murine brain, angiotensin II ( brain ͉ renin-angiotensin system ͉ zinc metalloproteases ͉ mercapto inhibitors ͉ blood pressure

Objective-Despite great advances in our knowledge, atherosclerosis continues to kill more people than any other disease in the Western world. This is because our means of identifying truly vulnerable patients is limited. Prediction of atherosclerotic plaque rupture may be addressed by MRI of activated matrix metalloproteinases (MMPs), a family of enzymes that have been implicated in the vulnerability of plaques prone to rupture. This study evaluated the ability of the novel gadolinium-based MRI contrast agent P947 to target MMPs in atherosclerotic plaques. Methods and Results-The affinity of P947 toward activated MMPs was demonstrated in vitro. The affinity and specificity of P947 toward matrix metalloproteinase (MMP)-rich plaques was evaluated both in vivo using ApoE Ϫ/Ϫ mice and ex vivo in hyperlipidemic rabbits. Gadolinium content quantification and MRI showed a preferential accumulation of P947 in atherosclerotic lesions compared with the nontargeted reference compound, Gd-DOTA. The ex vivo assay on rabbit plaques revealed a higher uptake of P947. Moreover, using human carotid artery endarterectomy specimens, P947 facilitated discrimination between histologically defined MMP-rich and MMP-poor plaques. An in vivo MRI investigation in mice revealed that P947 greatly improved the ability to visualize and delineate atherosclerotic plaques. Conclusions-P947 may be a useful tool for the detection and characterization of the MMP-rich atherosclerotic plaques. (Arterioscler Thromb Vasc Biol. 2008;28:425-432)Key Words: atherosclerosis Ⅲ matrix metalloproteinases Ⅲ MRI Ⅲ atherosclerotic plaque Ⅲ molecular imaging M olecular imaging is a promising modality for assessment of atherosclerotic plaque composition. 1 It may enable the detection of biological markers whose expression is directly related to the pathophysiological status of the lesions. 2,3 Recently, MRI has been used to assess activated plaques by detecting human macrophages with ultra-small superparamagnetic particles of iron oxide (Sinerem®), 4 rabbit angiogenesis with AlphaVbeta3 targeting nanoparticles, 5 rabbit thrombosis with a fibrin-binding contrast agent (EP-1873), 6 and murine macrophages with scavenger receptortargeted immunomicelles. 7 Finally, apoptotic plaque macrophages were visualized with [99m Tc]-labeled annexin V in carotid arteries of symptomatic patients. 8 By applying high-resolution multi-contrast in vivo MRI, some features of vulnerability, such as cap rupture, large necrotic core, or intraplaque hemorrhage, have become detectable in human carotid arteries. 9 Molecular imaging may substantially improve the accuracy of MRI detection by selectively revealing specific markers of instability. One such marker is represented by matrix metalloproteinases (MMPs), which are overexpressed in prone-to-rupture atherosclerotic lesions as a consequence of inflammation. 10 MMPs promote plaque destabilization by degrading the fibrillar collagen of the fibrous cap and are overexpressed in the shoulder regions of human atherosclerotic plaques, the most ...

Autotaxin (ATX) is a secreted enzyme playing a major role in the production of lysophosphatidic acid (LPA) in blood through hydrolysis of lysophosphatidyl choline (LPC). The ATX-LPA signaling axis arouses a high interest in the drug discovery industry as it has been implicated in several diseases including cancer, fibrotic diseases, and inflammation, among others. An imidazo[1,2-a]pyridine series of ATX inhibitors was identified out of a high-throughput screening (HTS). A cocrystal structure with one of these compounds and ATX revealed a novel binding mode with occupancy of the hydrophobic pocket and channel of ATX but no interaction with zinc ions of the catalytic site. Exploration of the structure-activity relationship led to compounds displaying high activity in biochemical and plasma assays, exemplified by compound 40. Compound 40 was also able to decrease the plasma LPA levels upon oral administration to rats.