PET of tumor CXCR4 expression with 4-18F-T140.
PET of tumor CXCR4 expression with 4-18F-T140.
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DOI：
10.2967/jnumed.110.079418
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发表时间：
2010-11
期刊：
影响因子：
--
通讯作者：
Chen X
中科院分区：
文献类型：
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作者：
Jacobson O;Weiss ID;Kiesewetter DO;Farber JM;Chen X
趋化因子受体CXCR4在癌症中的表达已被证明与肿瘤侵袭性和不良预后相关，也可能有助于表达其配体SDF-1的器官的转移播种。然而，目前还没有完全优化的PET试剂用于检测肿瘤细胞在体内的CXCR4表达。本研究旨在开发一种稳定的，18f标记的肽，能够在体内定量癌症中的CXCR4。4- f -苯甲酰- tn14003 （4- f - t140）是一种在赖氨酸残基的ε-氨基上具有1-（4,4-二甲基-2,6-二氧环己基）乙基保护基团的CXCR4短肽拮抗剂，通过N-琥珀酰-米基-4- 18f -氟苯甲酸偶联得到18f -氟化物，然后脱保护得到仅在N端α-胺上标记的4- f - t140。进行了4-18F-T140的细胞结合、迁移、生物分布和小动物PET研究。4-F-T140通过与n -琥珀酰酰-4- 18f -氟苯甲酸盐偶联进行放射性标记，从合成开始计算衰变校正后的总放射化学产率为15%±5%。测定的平均比活性（±SD）为7±2 GBq/μmol(0.19±0.05 Ci/μmol)，放射化学纯度大于99%。在体内和体外均发现4-18F-T140与红细胞特异性结合。少量冷的4-F-T140阻断了4-18F-T140与红细胞的结合，导致中国仓鼠卵巢(CHO)-CXCR4肿瘤对4-18F-T140的摄取增加。注射10 μg冷4-F-T140后3 h的生物分布实验显示，CHO-CXCR4肿瘤的每克注射剂量为3.03±0.31，肿瘤与血液比为27.1±8.7，肿瘤与肌肉比为21.6±7.1。PET研究显示cxcr4转染的CHO肿瘤清晰可见，而cxcr4阴性的CHO肿瘤则不可见。4-18F-T140可作为PET示踪剂成像肿瘤中CXCR4的表达，具有较高的肿瘤与背景比。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。
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, 18F-labeled peptide that enables in vivo quantification of CXCR4 in cancer. 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 18F-fluoride via N-succini-midyl-4-18F-fluorobenzoate conjugation, followed by deprotection to give 4-18F-T140 that was exclusively labeled on the α-amine at the N terminus. Cell binding, migration, biodistribution, and small-animal PET studies of 4-18F-T140 were performed. 4-F-T140 was radiolabeled by coupling with N-succinimidyl-4-18F-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 radio-chemical purity was greater than 99%. 4-18F-T140 was found to bind specifically to red blood cells in vitro and in vivo. The binding of 4-18F-T140 to red blood cells was blocked with a small amount of cold 4-F-T140, which led to higher uptake of 4-18F-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. 4-18F-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.