Abstract
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Objectives Matrix metalloproteinases (MMPs) play a major role in tissue remodeling and their imaging can potentially lead to better management of patients with cardiovascular diseases, including aneurysm, cardiomyopathy and atherosclerosis. The feasibility of vascular MMP imaging has been demonstrated using RP805, a 99mTc-labeled panMMP inhibitor, but this required imaging at relatively late time points. We have developed a novel MMP-targeted tracer, RYM, with potentially improved pharmacokinetics for vascular imaging. RYM is a rationally designed hydroxamate-based panMMP inhibitor containing a HYNIC group for Tc-99m radiolabeling. In this study we evaluated 99mTc-RYM biodistribution, binding to aneurysm and in vivo specificity.
Methods Biodistribution at 2 h post-injection (p.i.) and blood clearance were evaluated in C57Bl/6J mice injected with 0.5 mCi of 99mTc-RYM (n = 6) or 99mTc-RP805 (n = 6). In vivo targeting to aneurysm and specificity of 99mTc-RYM was evaluated in high-fat fed apolipoprotein E-deficient mice, 4 weeks after carotid aneurysm induction through peri-adventital application of CaCl2. The animals were injected with 0.3 mCi of 99mTc-RYM with (n = 3) or without (n = 4) pre-injection of a non-labeled RYM analog. This was followed by quantitative autoradiography of arterial tracer uptake at 2 h p.i.
Results 99mTc-RYM showed a lower blood pool activity compared to 99mTc-RP805 at 1 and 2 h p.i. [1.3 ± 0.4 vs 2.8 ± 1.2 % injected dose (ID)/mL and 1.0 ± 0.4 vs 1.8 ± 0.7 %ID/mL, respectively, p < 0.05 for both] and lower hepatobiliary excretion (bile: 1.5 ± 0.3 vs 17.8 ± 13.3 %ID/g, p < 0.05); tissue uptake was higher in several collected tissues, but not in control aorta (6.0 ± 1.4 vs 8.4 ± 1.9 %ID/g, p < 0.05). In carotid aneurysm, shown to display high MMP expression and activity, 99mTc-RYM uptake was higher than in aorta (3.2 ± 1.3 vs 2.0 ± 0.2 ×10-3 %ID/mm2, p < 0.05). Pre-injection of an excess of unlabeled competitor lead to 46% reduction in aneurysm-to-aorta relative uptake, demonstrating uptake specificity.
Conclusions The novel hydroxamate-based panMMP inhibitor-derived tracer, 99mTc-RYM, demonstrated improved pharmacokinetics for vascular imaging and specific in vivo binding to aneurysm. These data support further development of this agent for clinical translation.