Development of a ¹¹¹In-labeled peptide derivative targeting a chemokine receptor, CXCR4, for imaging tumors

Abstract 

The chemokine receptor CXCR4 is highly expressed in tumor cells and plays an important role in tumor metastasis. The aim of this study was to develop a radiopharmaceutical for the imaging of CXCR4-expressing tumors in vivo. Based on structure–activity relationships, we designed a 14-residue peptidic CXCR4 inhibitor, Ac-TZ14011, as a precursor for radiolabeled peptides. For ¹¹¹In-labeling, diethylenetriaminepentaacetic acid (DTPA) was attached to the side chain of d-Lys⁸ which is distant from the residues indispensable for the antagonistic activity. In-DTPA-Ac-TZ14011 inhibited the binding of a natural ligand, stromal cell-derived factor-1α, to CXCR4 in a concentration-dependent manner with an IC₅₀ of 7.9 nM (Ac-TZ14011: 1.2 nM). In biodistribution experiments, more ¹¹¹In-DTPA-Ac-TZ14011 accumulated in the CXCR4-expressing tumor than in blood or muscle. Furthermore, the tumor-to-blood and tumor-to-muscle ratios were significantly reduced by coinjection of Ac-TZ14011, indicating a CXCR4-mediated accumulation in tumor. These findings suggested that ¹¹¹In-DTPA-Ac-TZ14011 would be a potential agent for the imaging of CXCR4 expression in metastatic tumors in vivo.

Keywords: CXCR4, Peptide radiopharmaceutical, Indium-111, Metastatic tumor