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Preclinical Evaluation of RYM1, a Matrix Metalloproteinase-Targeted Tracer for Imaging Aneurysm
Jakub Toczek1,2, Yunpeng Ye1,2, Kiran Gona1,2
1Cardiovascular Molecular Imaging Laboratory, Section of Cardiovascular Medicine and Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut.
Abstract:
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.
Insights
A new imaging tracer, 99mTc-RYM1, effectively detects inflammation and matrix metalloproteinase (MMP) activity in abdominal aortic aneurysms. This tracer shows improved blood clearance and higher specificity for aneurysm detection in preclinical models.
Area of Science:
- Molecular imaging
- Vascular biology
- Radiochemistry
Background:
- Matrix metalloproteinases (MMPs) are crucial in abdominal aortic aneurysm (AAA) development.
- MMP-targeted imaging offers insights into AAA vessel wall changes.
- Effective AAA imaging requires sensitive tracers with rapid blood clearance.
Purpose of the Study:
- To develop and preclinically evaluate a novel pan-MMP tracer, 99mTc-RYM1, for AAA imaging.
- To compare the performance of 99mTc-RYM1 with a conventional tracer, 99mTc-RP805.
Main Methods:
- Synthesis and 99mTc-labeling of the novel macrocyclic hydroxamate-based pan-MMP inhibitor RYM1.
- Evaluation of radiochemical stability, blood kinetics, and biodistribution in murine models.
- Assessment of tracer binding, specificity, and in vivo imaging via SPECT/CT in aneurysm models.
Main Results:
- 99mTc-RYM1 demonstrated nanomolar MMP inhibition and radiochemical stability.
- The tracer exhibited rapid renal clearance and lower in vivo blood levels than 99mTc-RP805.
- SPECT/CT imaging revealed higher 99mTc-RYM1 uptake in AAA, correlating with MMP activity and inflammation markers.
Conclusions:
- The novel tracer 99mTc-RYM1 possesses favorable pharmacokinetics for vascular imaging.
- 99mTc-RYM1 enables specific detection of inflammation and MMP activity in abdominal aortic aneurysms.
- This tracer holds promise for early detection and monitoring of AAA.