title: 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-Lys(8) 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-1alpha, 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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Hanaoka
authors.forename: Takahiro
authors.initials: T
authors.lastname: Mukai
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Tamamura
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Mori
authors.forename: Seigo
authors.initials: S
authors.lastname: Ishino
authors.forename: Kazuma
authors.initials: K
authors.lastname: Ogawa
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Iida
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Doi
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Fujii
authors.forename: Hideo
authors.initials: H
authors.lastname: Saji
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods; D015195:Drug Design; D005260:Female; D007553:Isotope Labeling / Q000379:methods; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000378:metabolism*; D009928:Organ Specificity; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism*; D004369:Pentetic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D010455:Peptides / Q000138:chemical synthesis / Q000493:pharmacokinetics; D010456:Peptides, Cyclic / Q000737:chemistry / Q000493:pharmacokinetics*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D019707:Receptors, Chemokine / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: C512980:111indium-DTPA-Ac-TZ14011; D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D010455:Peptides; D010456:Peptides, Cyclic; D019275:Radiopharmaceuticals; D019707:Receptors, Chemokine; D004369:Pentetic Acid