CCR2 Positron Emission Tomography for the Assessment of Abdominal Aortic Aneurysm Inflammation and Rupture Prediction

Abstract

Background: The monocyte chemoattractant protein-1/CCR2 (chemokine receptor 2) axis plays an important role in abdominal aortic aneurysm (AAA) pathogenesis, with effects on disease progression and anatomic stability. We assessed the expression of CCR2 in a rodent model and human tissues, using a targeted positron emission tomography radiotracer ( 64 Cu-DOTA-ECL1i). Methods: AAAs were generated in Sprague-Dawley rats by exposing the infrarenal, intraluminal aorta to PPE (porcine pancreatic elastase) under pressure to induce aneurysmal degeneration. Heat-inactivated PPE was used to generate a sham operative control. Rat AAA rupture was stimulated by the administration of β-aminopropionitrile, a lysyl oxidase inhibitor. Biodistribution was performed in wild-type rats at 1 hour post tail vein injection of 64 Cu-DOTA-ECL1i. Dynamic positron emission tomography/computed tomography imaging was performed in rats to determine the in vivo distribution of radiotracer. Results: Biodistribution showed fast renal clearance. The localization of radiotracer uptake in AAA was verified with high-resolution computed tomography. At day 7 post-AAA induction, the radiotracer uptake (standardized uptake value [SUV]=0.91±0.25) was approximately twice that of sham-controls (SUV=0.47±0.10; P <0.01). At 14 days post-AAA induction, radiotracer uptake by either group did not significantly change (AAA SUV=0.86±0.17 and sham-control SUV=0.46±0.10), independent of variations in aortic diameter. Competitive CCR2 receptor blocking significantly decreased AAA uptake (SUV=0.42±0.09). Tracer uptake in AAAs that subsequently ruptured (SUV=1.31±0.14; P <0.005) demonstrated uptake nearly twice that of nonruptured AAAs (SUV=0.73±0.11). Histopathologic characterization of rat and human AAA tissues obtained from surgery revealed increased expression of CCR2 that was co-localized with CD68 + macrophages. Ex vivo autoradiography demonstrated specific binding of 64 Cu-DOTA-ECL1i to CCR2 in both rat and human aortic tissues. Conclusions: CCR2 positron emission tomography is a promising new biomarker for the noninvasive assessment of AAA inflammation that may aid in associated rupture prediction.

Imaging Inflammation with Positron Emission Tomography

“…The authors later compared 68 Ga- to 64 Cu-labelled ECL1i in cardiac injury and found comparable radiotracer uptake in the ischemic area [ 101 ]. Recently, the group also reported proof-of-concept for 64 Cu-DOTA-ECL1i PET in the detection of abdominal aortic aneurysm (AAA) [ 36 ] and pulmonary fibrosis [ 37 ] in rodent models and human tissue. Remarkably, 64 Cu-DOTA-ECL1i uptake was twice as high in AAA that subsequently ruptured compared to non-ruptured AAA.…”

“…Mainly expressed on pro-inflammatory monocytes, natural killer cells and T cells Lung inflammation [34], cardiac injury [35], abdominal aortic aneurysm [36], pulmonary fibrosis [37] Promising [38], atherosclerosis [39], vascular inflammation [40,41], rheumatoid arthritis [42][43][44]…”

Targeting the Extracellular Matrix in Abdominal Aortic Aneurysms Using Molecular Imaging Insights

“…NC100692, a 99 mTc-cyclic RGD tracer for microSPECT-CT displayed increased uptake in murine carotid aneurysms and a correlation with inflammatory activity [ 36 ]. English et al recently developed a specific agent of chemokine receptor type 2 (CCR2) with the PET tracer 64 Cu-DOTA-ECL1i [ 37 ]. CCR2 is expressed in macrophages/monocytes and mediates the migration of leukocytes to the inflammatory event in the vessel wall after injury.…”

“…CCR2 is expressed in macrophages/monocytes and mediates the migration of leukocytes to the inflammatory event in the vessel wall after injury. In induced AAA in Sprague-Dawley rats, 64 Cu-DOTA-ECL1i showed significantly increased uptake compared with sham controls and compared with aneurysms that did not rupture during progression [ 37 ].…”

Radionuclide molecular imaging of abdominal aortic aneurysms for risk stratification and non‐invasive therapy assessment

“…7 In the porcine pancreatic elastase-induced AAA murine model, earlystage [ 64 Cu]DOTA-ECL1i uptake, which reflects binding to chemokine receptor 2, may facilitate rupture prediction. 8 [ 18 F]fluoromethylcholine, which is typically utilised in prostate cancer staging to identify choline uptake, may also be useful to identify concurrent AAA in patients with prostate cancer. 9 Regarding the prospect of SPECT, RP805, a [ 99m Tc]-labelled radiotracer that targets matrix metalloproteinases (MMPs), has been used to demonstrate that MMP-targeted SPECT may indicate aortic wall inflammation and help predict expansion or rupture in AAA.…”