Session M5.3

Assessment of Natriuretic Peptide Clearance Receptor with Positron Emission Tomography in a Cardiovascular Disease Model

Y Liu*, R Rossin, D Abendschein, GE Woodard, J Zheng,
K McCommis, PK Woodard, MJ Welch

Washington University
St. Louis, MO, USA

Cardiovascular molecular imaging is used to detect and quantify, at the molecular and cellular level, the pathways that regulate heart and blood vessel function, and to understand abnormalities in these pathways. Natriuretic peptides (NPs) can acts as a potent inhibitor of vascular smooth muscle cell migration and proliferation through activation of the clearance receptor (NPR-C). In this study, a Cu-64 labeled NP fragment was employed as a probe for non-invasive imaging with positron emission tomography (PET) of NPR-C receptor expression in developed cardiovascular disease animal models. Hind limb ischemia (HLI), which has been shown to stimulate angiogenesis, was induced in male C57BL/6 mice by ligation and excision of a segment of the right femoral artery. A sham surgery was performed on the left femoral as a control. Atherosclerosis animal model was developed from male New Zealand white rabbits fed with cholesterol-rich diet before the right femoral artery was double-injured by air dessication and balloon overstretching, respectively, overtime. CANF (atrial natriuretic factor), which is a C-type NP analog, functionalized with DOTA and labeled with 64-Cu was used as radiotracer for the PET imaging. A 1 h dynamic scan was collected on the microPET Focus-220. Fiducial markers were attached to the scanner bed for PET/CT/MR co-registration. Histopathologic imaging and immunohistochemistry (IHC) of the ex vivo tissue were performed to confirm the presence of NPR-C receptors. PET imaging after I.V. co-injection of CANF peptide as a blocking agent with 64Cu-DOTA-CANF (100:1 mole ratio) was performed to prove the receptor mediated tracer uptake. PET imaging clearly showed the tracer uptake in the injured sites with virtually weak uptake observed in the control sites in both models. The standard uptake value ratio of injury/control was 2.34±0.41 (n=4) and could be significantly blocked to 1.24±0.26 (n=4) (p<0.005). In the rabbit atherosclerotic model, the highest signal/background ratio (3.39±0.78) was observed after the first injury and the PET blocking studies proved the receptor mediated tracer uptake at the injury artery. IHC blocking studies demonstrated the presence of NPR-C receptor on the injured sites. This study shows NPR-C receptors are upregulated in the ischemic hind limb of mice and rabbit atherosclerotic-like plaque. The PET imaging shows 64Cu-DOTA-CANF is a promising candidate tracer for molecular imaging of NPR-C receptors in the cardiovascular disease animal models.
Research Support: This work is supported by the NIH as a Program of Excellence in Nanotechnology (HL080729). The production of 64-Cu is supported by a NCI grant (CA86307).

(Abstract Control Number: 199)