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 the structure of CXCR4 antagonists TIQ-15, had designed by computer simulation as a PET tracer for imaging activated macrophages within the atherosclerotic lesions. The aim of this study was to evaluate the biological characteristics of [68Ga]-APD, and compared with the PET tracers targeting atherosclerotic lesion such as [18F]-FDG, [18F]-NaF, and [68Ga]-Pentixafor in apolipoprotein-E-deficient (ApoE−/−) mice.
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℃human serum. After being injected from tail vein on ApoE−/− atherosclerotic mice model, hydrophilic [68Ga]-APD was quickly eliminate from the kidney and bladder. [68Ga]-APD could accumulate in the atherosclerotic aorta site and CXCR4 expression organs. 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 within 1 hour. However, [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.
In vivo evaluation of CXCR4 expression in ApoE−/− mice revealed the uptake of [68Ga]-APD mainly accumulated in the atherosclerotic aorta site. Moreover, the TBR of [68Ga]-APD was 8 times higher than [68Ga]-Pentixafor, a radiotracer targeting CXCR4 and under phase II clinical trial, indicating this novel tracer [68Ga]-APD is more feasible as a surrogate marker for inflammatory atherosclerosis.