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Published on: February 23, 2020
Positron Emission Tomography Imaging of Vessel Wall Matrix Metalloproteinase Activity in Abdominal Aortic Aneurysm
Jakub Toczek1,2, Kiran Gona1,2, Yongjian Liu3
1Cardiovascular Molecular Imaging Laboratory, Section of Cardiovascular Medicine and Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT (J.T., K.G., A.A., M.G., D.O., G.K., M.S.).
Background:
Matrix metalloproteinases (MMPs) play a key role in the pathogenesis of abdominal aortic aneurysm (AAA). Imaging aortic MMP activity, especially using positron emission tomography to access high sensitivity, quantitative data, could potentially improve AAA risk stratification. Here, we describe the design, synthesis, characterization, and evaluation in murine AAA and human aortic tissue of a first-in-class MMP-targeted positron emission tomography radioligand, 64Cu-RYM2.
Methods:
The broad spectrum MMP inhibitor, RYM2 was synthetized, and its potency as an MMP inhibitor was evaluated by a competitive inhibition assay. Toxicology studies were performed. Tracer biodistribution was evaluated in a murine model of AAA induced by angiotensin II infusion in Apolipoprotein E-deficient mice. 64Cu-RYM2 binding to normal and aneurysmal human aortic tissues was assessed by autoradiography.
Results:
RYM2 functioned as an MMP inhibitor with nanomolar affinities. Toxicology studies showed no adverse reaction in mice. Upon radiolabeling with Cu-64, the resulting tracer was stable in murine and human blood in vitro. Biodistribution and metabolite analysis in mice showed rapid renal clearance and acceptable in vivo stability. In vivo positron emission tomography/computed tomography in a murine model of AAA showed a specific aortic signal, which correlated with ex vivo measured MMP activity and Cd68 gene expression. 64Cu-RYM2 specifically bound to normal and aneurysmal human aortic tissues in correlation with MMP activity.
Conclusions:
64Cu-RYM2 is a first-in-class MMP-targeted positron emission tomography tracer with favorable stability, biodistribution, performance in preclinical AAA, and importantly, specific binding to human tissues. These data set the stage for 64Cu-RYM2-based translational imaging studies of vessel wall MMP activity, and indirectly, inflammation, in AAA.
Insights
A novel positron emission tomography tracer, 64Cu-RYM2, targets matrix metalloproteinases (MMPs) to image abdominal aortic aneurysm (AAA) activity. This tracer shows promise for improved AAA risk stratification and understanding vessel wall inflammation.
Area of Science:
- Cardiovascular Imaging
- Radiochemistry
- Molecular Imaging
Background:
- Matrix metalloproteinases (MMPs) are crucial in abdominal aortic aneurysm (AAA) development.
- Positron emission tomography (PET) offers sensitive, quantitative imaging of MMP activity for AAA risk stratification.
Purpose of the Study:
- To develop and evaluate a novel MMP-targeted PET radioligand, 64Cu-RYM2, for imaging AAA.
- To assess the tracer's performance in preclinical models and human tissues.
Main Methods:
- Synthesized and characterized the broad-spectrum MMP inhibitor RYM2.
- Evaluated 64Cu-RYM2's stability, biodistribution, and in vivo performance in a murine AAA model.
- Assessed 64Cu-RYM2 binding in human aortic tissues using autoradiography.
Main Results:
- RYM2 demonstrated nanomolar MMP inhibitory potency with no observed toxicity.
- 64Cu-RYM2 exhibited favorable stability, rapid renal clearance, and acceptable in vivo characteristics.
- PET/CT imaging in mice revealed specific aortic uptake correlating with MMP activity and Cd68 expression.
- The tracer specifically bound to human aortic tissues, correlating with MMP activity.
Conclusions:
- 64Cu-RYM2 is a first-in-class MMP-targeted PET tracer for AAA.
- It shows excellent preclinical performance and specific binding to human tissues.
- This tracer facilitates translational imaging studies of AAA vessel wall MMP activity and inflammation.
