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Molecular imaging of matrix metalloproteinase activation to predict murine aneurysm expansion in vivo.

ABSTRACT: Rupture and dissection are major causes of morbidity and mortality in arterial aneurysm and occur more frequently in rapidly expanding aneurysms. Current imaging modalities provide little information on aneurysm beyond size. Matrix metalloproteinase (MMP) activation plays a key role in the pathogenesis of aneurysm. We investigated whether imaging MMP activation in aneurysm helps predict its propensity to expansion.We used a model of carotid aneurysm in apolipoprotein E-deficient (apoE(-/-)) mice. Radiotracers with specificity for activated MMPs were used to detect and quantify MMP activation by micro-SPECT/CT in vivo. Tracer uptake was confirmed by autoradiography and gamma-well counting, and specificity was demonstrated using an excess of unlabeled precursor and a specific MMP inhibitor.We demonstrated that several MMPs are expressed with distinct temporal patterns in aneurysm. Significant focal uptake was observed in aneurysmal carotid arteries, peaking at 4 wk after aneurysm induction. In a group of animals imaged serially at 2 and 4 wk after aneurysm induction, MMP tracer uptake at 2 wk correlated well with the vessel area assessed by histology at 4 wk.Molecular imaging of MMP activation is a useful experimental, and potentially clinical, tool to noninvasively predict the propensity of an aneurysm to expansion in vivo.

SUBMITTER: Razavian M

PROVIDER: S-EPMC2908304 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Molecular imaging of matrix metalloproteinase activation to predict murine aneurysm expansion in vivo.

Razavian Mahmoud M Zhang Jiasheng J Nie Lei L Tavakoli Sina S Razavian Niema N Dobrucki Lawrence W LW Sinusas Albert J AJ Edwards D Scott DS Azure Michael M Sadeghi Mehran M MM

Journal of nuclear medicine : official publication, Society of Nuclear Medicine 20100616 7

<h4>Unlabelled</h4>Rupture and dissection are major causes of morbidity and mortality in arterial aneurysm and occur more frequently in rapidly expanding aneurysms. Current imaging modalities provide little information on aneurysm beyond size. Matrix metalloproteinase (MMP) activation plays a key role in the pathogenesis of aneurysm. We investigated whether imaging MMP activation in aneurysm helps predict its propensity to expansion.<h4>Methods</h4>We used a model of carotid aneurysm in apolipop ...[more]

PMID: 20554725

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Project description: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 99mTc. Radiochemical stability of 99mTc-RYM1 was evaluated by radio-high-performance liquid chromatography analysis. Tracer blood kinetics and biodistribution were compared with 99mTc-RP805 in C57BL/6J mice (n = 10). 99mTc-RYM1 binding to aneurysm and specificity were evaluated by quantitative autoradiography in apolipoprotein E-deficient (apoE-/-) mice with CaCl2-induced carotid aneurysm (n = 11). Angiotensin II-infused apoE-/- (n = 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. 99mTc-RYM1 was radiochemically stable in mouse blood for 5 h and demonstrated rapid renal clearance and lower blood levels in vivo compared with 99mTc-RP805. 99mTc-RYM1 binding to aneurysm and its specificity were shown by autoradiography in carotid aneurysm. Angiotensin II infusion in apoE-/- mice for 4 wk resulted in AAA formation in 36% (4/11) of surviving animals. In vivo 99mTc-RYM1 small-animal SPECT/CT images showed higher uptake of the tracer in AAA than nondilated aortae. Finally, aortic uptake of 99mTc-RYM1 in vivo correlated with aortic MMP activity and CD68 expression. Conclusion: The newly developed pan-MMP inhibitor-based tracer 99mTc-RYM1 displays favorable pharmacokinetics for early vascular imaging and enables specific detection of inflammation and MMP activity in aneurysm.

Dataset Information

Molecular imaging of matrix metalloproteinase activation to predict murine aneurysm expansion in vivo.

Publications

Molecular imaging of matrix metalloproteinase activation to predict murine aneurysm expansion in vivo.

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