Preclinical cardiovascular research using noninvasive radionuclide and hybrid imaging systems has been extensively developed in recent years. Single photon emission computed tomography (SPECT) is based on the molecular tracer principle and is an established tool in noninvasive imaging. SPECT uses gamma cameras and collimators to form projection data that are used to estimate (dynamic) 3-D tracer distributions in vivo. Recent developments in multipinhole collimation and advanced image reconstruction have led to sub-millimetre and sub-half-millimetre resolution SPECT in rats and mice, respectively. In this article we review applications of microSPECT in cardiovascular research in which information about the function and pathology of the myocardium, vessels and neurons is obtained. We give examples on how diagnostic tracers, new therapeutic interventions, pre- and postcardiovascular event prognosis, and functional and pathophysiological heart conditions can be explored by microSPECT, using small-animal models of cardiovascular disease.
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...
Background Abdominal aortic aneurysm (AAA) rupture risk is currently determined based on size and symptoms. This approach does not address the rupture risk associated with small aneurysms. Given the role of matrix metalloproteinases (MMPs) in AAA weakening and rupture, we investigated the potential of MMP-targeted imaging for detection of aneurysm biology and prediction of outcome in a mouse model of AAA with spontaneous rupture. Methods and Results Fifteen week-old mice (n=66) were infused with angiotensin II for four weeks to induce AAA. Saline-infused mice (n=16) served as control. The surviving animals underwent in vivo MMP-targeted microSPECT/CT imaging, using RP805, a 99mTc-labeled MMP-specific tracer, followed by ex vivo planar imaging, morphometry and gene expression analysis. RP805 uptake in suprarenal aorta on microSPECT images was significantly higher in animals with AAA, as compared with angiotensin II-infused animals without AAA or control animals. CD68 expression and MMP activity were increased in AAA and significant correlations were noted between RP805 uptake and CD68 expression or MMP activity, but not aortic diameter. A group of angiotensin II-infused animals (n=24) were imaged at 1 week and were followed for an additional three weeks. RP805 uptake in suprarenal aorta at 1 week was significantly higher in mice that later developed rupture/AAA. Furthermore, tracer uptake at 1 week correlated with aortic diameter at 4 weeks. Conclusions MMP-targeted imaging reflects vessel wall inflammation and can predict future aortic expansion or rupture in murine AAA. If confirmed in humans, this may provide a new paradigm for AAA risk stratification.
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