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Imaging the Cytokine Receptor CXCR4 in Atherosclerotic Plaques with [68Ga]-APD: A Novel Agent on Computer Simulation Approach

Chien-Chung Hsia*, Chung-Hsin Yeh, Chun-Tang Chen, Cheng Liang Peng

Introduction: C-X-C motif chemokine receptor 4 (CXCR4) plays a prominent role in inflammation, atherosclerosis, and cancer biology. Therefore, CXCR4 represents a promising target for molecular imaging in cardiovascular diseases such as atherosclerosis and arterial wall injury.CXCR4 and its cognate ligand, stromal cell–derived factor 1α (SDF- 1α), induced monocyte recruitment to the injured endothelium and subsequent plaque formation is the crucial progression of atherosclerosis. CXCR4 was been proved to be intensively expressed on monocytes/macrophage. [⁶⁸Ga]-APD, based on CXCR4 antagonists TIQ-15, had designed as a PET tracer for imaging atherosclerosis. The aim of this study was to evaluate the biological characteristics of [⁶⁸Ga]-APD, and compared with [¹⁸F]-FDG, [¹⁸F]- NaF, and [⁶⁸Ga]-Pentixafor.

Results: The specification and quality of APD was identified by Mass, NMR and HPLC. After being labeled with Ga-68 under acetate buffer (pH=5.5), radiochemical purity was over 90% and stable for more than 4 hours in 37°C human serum. After being injected from tail vein on apolipoprotein-E-deficient (ApoE-/-) atherosclerotic mice, hydrophilic [⁶⁸Ga]-APD was quickly eliminate from the kidney and bladder and accumulate in the atherosclerotic aorta. The highest target/background ratio (TBR) on atherosclerotic sites were 17.68 ± 0.71 (n=3) on high-fat diet ApoE-/- mice for 12 weeks after [⁶⁸Ga]-APD injection about 1 hour. However, the TBR of [⁶⁸Ga]-Pentixafor was only 2.06 ± 0.67 (n=3) on the same mice model. Competitive study represented that CXCR4 antagonist AMD3465 could effectively block the uptake of [⁶⁸Ga]-APD on the atherosclerotic site and CXCR4 expression organs. Comparing with [¹⁸F]-FDG and [¹⁸F]-NaF, [⁶⁸Ga]-APD represented relatively better TBR and specificity on the imaging of atherosclerotic lesions.

Conclusion: In vivo evaluation of CXCR4 expression in ApoE-/- mice revealed the high TBR of [⁶⁸Ga]-APD on the atherosclerotic aorta and better than [⁶⁸Ga]-Pentixafor. These evidences represented its feasible as a surrogate marker for inflammatory atherosclerosis.