Imaging the Cytokine Receptor CXCR4 in Atherosclerotic Plaques with the Radiotracer ⁶⁸Ga-Pentixafor for PET

Abstract

68 Ga-pentixafor is a radiotracer for 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 noninjured rabbits fed a chow diet were used as controls. Rabbits were imaged on a PET/MR system after injection of 68 Ga-pentixafor (15 MBq/kg). Vascular signal was quantified as tissue-to-background ratio (TBR). Biodistribution and autoradiographic studies were performed 1 h after injection of 125 I-pentixafor (7.5 MBq/kg). In addition, blocking studies were performed in 2 atherosclerotic rabbits with preinjection of the CXCR4 inhibitor AMD3100. Tracer uptake was quantified on arterial cryosections using autoradiography and compared with CXCR4 and RAM-11 (macrophage) expression on adjacent histologic sections. Results: One hour after injection of 68 Ga-pentixafor, strong signals were detected in vivo with PET/MR imaging in atherosclerotic plaques of the abdominal aorta and right carotid artery as compared with normal control arteries (mean TBR 5 1.95 6 0.51 vs. 1.22 6 0.25 and mean TBR 5 1.24 6 0.38 vs. 0.96 6 0.37, respectively; P , 0.05 for both). Blocking studies with preinjection of a CXCR4 inhibitor reduced 125 I-pentixafor uptake in atherosclerotic plaques by approximately 40%. 125 I-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 (r 2 5 0.61; P , 0.05). Conclusion: 68 Ga-pentixafor allows for the noninvasive detection of CXCR4 expression in the vessel wall with PET and emerges as a potential alternative to 18 F-FDG for the assessment of macrophage infiltration in atherosclerotic plaques.

Integrating MRI and Chemokine Receptor CXCR4-Targeted PET for Detection of Leukocyte Infiltration in Complicated Urinary Tract Infections After Kidney Transplantation

“…The CXCR4/CXCL12 axis has a pivotal role in trafficking of leukocytes between bone marrow and sites of infection (10), providing the host with a mechanism to rapidly increase neutrophil delivery to sites of infection via chemokine secretion (21). In previous studies, 68 Ga-pentixafor has been used to quantify noninfectious inflammation (13,14), linking CXCR4 upregulation to CD68 1 macrophages and Ly6G 1 granulocytes (13). CXCR4 is expressed by a variety of immune cells including macrophages and neutrophils (10,21,22).…”

“…68 Ga-pentixafor has previously been applied to visualize CXCR-positive (CXCR 1 ) bone marrowderived cells in myeloproliferative diseases (11,12). 68 Ga-pentixafor has also been reported to specifically identify postinfarction myocardial inflammation mediated by CXCR4 1 leukocytes (13) and atherosclerotic plaque inflammation (14). Diffusion-weighted MRI has been shown to provide useful information for diagnosing and monitoring pyelonephritis foci in transplanted kidneys (15).…”

CXCR4 Ligands: The Next Big Hit?

“…Proof-of-concept visualization with this tracer could be demonstrated not only for several different hematologic and other neoplasms-including leukemia, lymphoma, multiple myeloma, adrenocortical carcinoma, and small cell lung cancer (Fig. 2) (72-77)-but also for other solid tumors and disease conditionssuch as splenosis, stroke, atherosclerosis, and myocardial infarction (78)(79)(80)(81)(82)(83)(84).…”

CXCR4-binding PET tracers link monocyte recruitment and endothelial injury in murine atherosclerosis

“…It is important to point out that an argument has been that a different tracer targeting CXCR4, 68 Ga-Pentixafor, has been reported to have the capacity to penetrate plaques and reach deeper macrophages therein (41). 68 Ga-Pentixafor is, in fact, a smaller molecule than our chemokine receptor-targeting tracers and thus may have distinct bioavailability.…”

“…To further investigate the hypothesis that CXCR4 signal reports the level of endothelial injury in atherosclerosis, we compared 64 Cu-DOTA-vMIP-II to 64 Cu-DOTA-FC131, a CXCR4 specific tracer. Although PET signals arising from CXCR4-specific tracer is already reported in atherosclerosis (41)(42)(43)(44), the plaque characteristics, or biological parameters of plaque activity, that may or may not correlate with its PET signal are still not fully understood. Similar to studies with the vMIP-II tracer ( Fig.…”