肿瘤 CXCR4 表达的 PET 检查采用 4-18F-T140。
PET of tumor CXCR4 expression with 4-18F-T140.
机构信息
Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland, USA.
出版信息
J Nucl Med. 2010 Nov;51(11):1796-804. doi: 10.2967/jnumed.110.079418. Epub 2010 Oct 18.
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.
目的
开发一种稳定的、（18）F 标记的肽，使肿瘤细胞中 CXCR4 的体内定量成为可能。
方法
用 N-琥珀酰亚胺-4-（18）F-氟代苯甲酸酯偶联，将含有赖氨酸 ε-氨基上 1-（4,4-二甲基-2,6-二氧环己基）乙基保护基的短肽 CXCR4 拮抗剂 4-F-苯甲酰基-TN14003（4-F-T140）进行（18）F 标记，然后脱保护得到仅在 N 端α-氨基上标记的 4-（18）F-T140。进行了 4-（18）F-T140 的细胞结合、迁移、生物分布和小动物 PET 研究。
结果
用 N-琥珀酰亚胺-4-（18）F-氟代苯甲酸酯偶联，从合成开始计算，总放射性化学产率为 15%±5%。平均测量比活度（±SD）为 7±2GBq/μmol（0.19±0.05Ci/μmol），放射化学纯度大于 99%。4-（18）F-T140 在体外和体内均发现能特异性结合红细胞。4-（18）F-T140 与红细胞的结合可被少量冷 4-F-T140 阻断，这导致中国仓鼠卵巢（CHO）-CXCR4 肿瘤对 4-（18）F-T140 的摄取增加。在注射后 3 小时加入 10μg 冷 4-F-T140 的生物分布实验中，CHO-CXCR4 肿瘤的摄取量为 3.03±0.31%注入剂量/克，肿瘤与血液的比值为 27.1±8.7，肿瘤与肌肉的比值为 21.6±7.1。PET 研究表明，CXCR4 转染的 CHO 肿瘤可以清晰显示，但 CXCR4 阴性的 CHO 肿瘤则不能。
结论
4-（18）F-T140 可用作 PET 示踪剂，用于成像肿瘤 CXCR4 的表达，具有高肿瘤与背景的比值。了解肿瘤是否表达或不表达 CXCR4，可能有助于确定适当的治疗和监测。
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