Assessment of CCR2 PET for abdominal aortic aneurysm rupture prediction and determination of treatment response

Introduction: Objectives: Abdominal aortic aneurysms (AAA) are a life-threatening degenerative vascular disease without any effective medical therapy or imaging approach to predict the risk of rupture. AAAs occur later in life and are especially prevalent in men over the age of 65, but are more likely to rupture in women. Previously, we evaluated the efficiency of chemokine receptor 2 (CCR2) targeting tracer ⁶⁴Cu-DOTA-ECL1i for imaging the AAA expansion and rupture in male rats. Herein, we established a AAA rupture model in rats, and evaluated how sensitive our CCR2 tracer can predict AAA expansion and rupture.

Methods: Methods: A surgical AAA induction model in Sprague-Dawley rats of intra-aortic exposure to pressurized porcine pancreatic elastase (PPE) was used. AAA rupture was stimulated by the administration of β-aminopropionitrile (BAPN). A CCR2 antagonist, RS504393, was administered via oral gavage at day 3 post AAA induction. Dynamic CCR2 PET/CT scans were performed at 45-60 min post tail vein injection in both antagonist treated and untreated animals with AAA to evaluate whether CCR2 signal intensity predicted AAA expansion and rupture. Histopathology, immunostaining, tissue zymography, and ELISA techniques were used to evaluate AAA tissue post-mortem. The CCR2-targeted PET imaging of AAA patients is being carried out under eIND 137620.

Results: Results: Compared to female animals with non-ruptured AAAs, CCR2 tracer uptake was significantly higher in females with ruptured AAAs (p<0.005, n=5-7), although overall AAA maximum diameter was unchanged. CCR2 inhibition caused AAA rupture rate in male animals to decrease from 56% (14/25) to 0% (0/15) at day 14 post treatment, and CCR2 PET signals were decreased on Day 6 (p<0.05, n=6) and day 14 (p<0.005, n=6). On the other hand, CCR2 inhibition in female rats demonstrated a decrease in rupture from 41% (14/32) to 20% (3/15), and CCR2 PET signals were decreased by 40% (p<0.001, n=5-8) at both day 6 and 14. Histopathology of RS504393-treated rats demonstrated reduced inflammation, preserved elastic layers and elastic laminae, minimal vascular smooth muscle cells loss, and compensatory medial hypertrophy. Immunostaining also showed significantly decreased CD68+ macrophages and modest CCR2 expression. Zymography and ELISA demonstrated reduced active MMP-9, IL-1 Beta, and IL-6 in rats treated with CCR2 antagonist. Moreover, in AAA patients, ⁶⁴Cu-DOTA-ECL1i showed significant uptake in the aneurysm.

Conclusions: Conclusions: CCR2 PET/CT signal appears to highly predict AAA risk of rupture in both male and female rats, and may provide a basis of enhanced AAA surveillance in human patients with AAAs that are prone to rupture. The sensitive detection of CCR2 indicates the potential of ⁶⁴Cu-DOTA-ECL1i for AAA theranostics.