Imaging the cytokine receptor CXCR4 in atherosclerotic plaques with the radiotracer ⁶⁸Ga-pentixafor for positron emission tomography

Abstract

⁶⁸Ga-pentixafor is a radiotracer for positron emission tomography (PET) that binds with nanomolar affinity to CXCR4. The CXCR4 receptor is expressed at the surface of inflammatory cells. The objective of the study was to analyze the ability of radiolabeled pentixafor to detect CXCR4 expression on inflammatory cells present in atherosclerotic plaques of an experimental rabbit model. Methods: Atherosclerotic plaques were induced by endothelial abrasion of the right carotid artery and abdominal aorta of 7 rabbits fed an atherogenic diet. Five non injured rabbits fed a chow diet were used as controls. Rabbits were imaged on a PET-MRI system after injection of 15 MBq/kg of ⁶⁸Ga-pentixafor. Vascular signal was quantified as tissue to background ratio (TBR). Biodistribution and autoradiographic studies were performed 1 hour after injection of 7.5 MBq/kg of ¹²⁵I-pentixafor. In addition, blocking studies were performed in two atherosclerotic rabbits with pre-injection of the CXCR4 inhibitor AMD3100. Tracer uptake was quantified on arterial cryosections using autoradiography and compared to CXCR4 and RAM-11 (macrophage) expression on adjacent histological sections. Results: One hour after injection of ⁶⁸Ga-pentixafor, strong signals were detected in vivo with PET-MRI in atherosclerotic plaques of the abdominal aorta and right carotid artery as compared to normal control arteries (average TBR = 1.95 ± 0.51 vs. 1.22 ± 0.25 and TBR = 1.24 ± 0.38 vs. 0.96 ± 0.37, respectively; P < 0.05 for both). Blocking studies with pre-injection of a CXCR4 inhibitor reduced ¹²⁵I-pentixafor uptake in atherosclerotic plaques by ~ 40 %. ¹²⁵I-pentixafor uptake in the vessel wall on autoradiographies was located in macrophage-rich regions of atherosclerotic plaques and correlated with the intensity of CXCR4 expression on corresponding cryosections (r2 = 0.61; P < 0.05). Conclusion: ⁶⁸Ga-pentixafor allows for the noninvasive detection of CXCR4 expression in the vessel wall with PET and emerges as a potential alternative to FDG for the assessment of macrophage infiltration in atherosclerotic plaques.