UNLABELLED: Expression of the chemokine receptor CXCR4 by cancers has been shown to correlate with tumor aggressiveness and poor prognosis and may also contribute to metastatic seeding of organs that express its ligand SDF-1. However, fully optimized PET agents for determining CXCR4 expression by tumor cells in vivo are not yet available. This study aims to develop a stable, (18)F-labeled peptide that enables in vivo quantification of CXCR4 in cancer. METHODS: 4-F-benzoyl-TN14003 (4-F-T140), a short peptide antagonist of CXCR4 with 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl protecting groups on the ε-amino groups of the lysine residues, was labeled with (18)F-fluoride via N-succinimidyl-4-(18)F-fluorobenzoate conjugation, followed by deprotection to give 4-(18)F-T140 that was exclusively labeled on the α-amine at the N terminus. Cell binding, migration, biodistribution, and small-animal PET studies of 4-(18)F-T140 were performed. RESULTS: 4-F-T140 was radiolabeled by coupling with N-succinimidyl-4-(18)F-fluorobenzoate, with an overall decay-corrected radiochemical yield of 15% ± 5% calculated from the start of synthesis. The mean measured specific activity (±SD) was 7 ± 2 GBq/μmol (0.19 ± 0.05 Ci/μmol), and radiochemical purity was greater than 99%. 4-(18)F-T140 was found to bind specifically to red blood cells in vitro and in vivo. The binding of 4-(18)F-T140 to red blood cells was blocked with a small amount of cold 4-F-T140, which led to higher uptake of 4-(18)F-T140 by Chinese hamster ovarian (CHO)-CXCR4 tumors. Biodistribution experiments at 3 h after injection with the addition of 10 μg of cold 4-F-T140 showed a 3.03 ± 0.31 percentage injected dose per gram uptake in CHO-CXCR4 tumors, with a tumor-to-blood ratio of 27.1 ± 8.7 and a tumor-to-muscle ratio of 21.6 ± 7.1. PET studies demonstrated clear visualization of CXCR4-transfected, but not CXCR4-negative, CHO tumors. CONCLUSION: 4-(18)F-T140 can be used as a PET tracer to image tumor expression of CXCR4, with a high tumor-to-background ratio. The knowledge of whether tumors express or do not express CXCR4 might be beneficial in determining appropriate treatment and monitoring.
UNLABELLED: Expression of the chemokine receptor CXCR4 by cancers has been shown to correlate with tumor aggressiveness and poor prognosis and may also contribute to metastatic seeding of organs that express its ligand SDF-1. However, fully optimized PET agents for determining CXCR4 expression by tumor cells in vivo are not yet available. This study aims to develop a stable, (18)F-labeled peptide that enables in vivo quantification of CXCR4 in cancer. METHODS:4-F-benzoyl-TN14003 (4-F-T140), a short peptide antagonist of CXCR4 with 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl protecting groups on the ε-amino groups of the lysine residues, was labeled with (18)F-fluoride via N-succinimidyl-4-(18)F-fluorobenzoate conjugation, followed by deprotection to give 4-(18)F-T140 that was exclusively labeled on the α-amine at the N terminus. Cell binding, migration, biodistribution, and small-animal PET studies of 4-(18)F-T140 were performed. RESULTS:4-F-T140 was radiolabeled by coupling with N-succinimidyl-4-(18)F-fluorobenzoate, with an overall decay-corrected radiochemical yield of 15% ± 5% calculated from the start of synthesis. The mean measured specific activity (±SD) was 7 ± 2 GBq/μmol (0.19 ± 0.05 Ci/μmol), and radiochemical purity was greater than 99%. 4-(18)F-T140 was found to bind specifically to red blood cells in vitro and in vivo. The binding of 4-(18)F-T140 to red blood cells was blocked with a small amount of cold 4-F-T140, which led to higher uptake of 4-(18)F-T140 by Chinese hamster ovarian (CHO)-CXCR4 tumors. Biodistribution experiments at 3 h after injection with the addition of 10 μg of cold 4-F-T140 showed a 3.03 ± 0.31 percentage injected dose per gram uptake in CHO-CXCR4 tumors, with a tumor-to-blood ratio of 27.1 ± 8.7 and a tumor-to-muscle ratio of 21.6 ± 7.1. PET studies demonstrated clear visualization of CXCR4-transfected, but not CXCR4-negative, CHO tumors. CONCLUSION: 4-(18)F-T140 can be used as a PET tracer to image tumor expression of CXCR4, with a high tumor-to-background ratio. The knowledge of whether tumors express or do not express CXCR4 might be beneficial in determining appropriate treatment and monitoring.
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