Suppr超能文献

三种用于正电子发射断层扫描(PET)成像缓激肽B1受体表达的68Ga标记的[去精氨酸10]胰激肽衍生物的比较研究。

Comparative studies of three 68Ga-labeled [Des-Arg10]kallidin derivatives for imaging bradykinin B1 receptor expression with PET.

作者信息

Lin Kuo-Shyan, Amouroux Guillaume, Pan Jinhe, Zhang Zhengxing, Jenni Silvia, Lau Joseph, Liu Zhibo, Hundal-Jabal Navjit, Colpo Nadine, Bénard François

机构信息

Department of Molecular Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada Department of Radiology, University of British Columbia, Vancouver, British Columbia, Canada; and.

Department of Molecular Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada.

出版信息

J Nucl Med. 2015 Apr;56(4):622-7. doi: 10.2967/jnumed.114.152132. Epub 2015 Mar 5.

Abstract

UNLABELLED

Bradykinin B1 receptor (B1R) is a G-protein-coupled receptor that is overexpressed in a variety of cancers. B1R is not expressed in healthy tissues, making it an attractive cancer imaging marker. Previously, we reported selective uptake of (68)Ga-P03034 ((68)Ga-DOTA-dPEG2-Lys-Arg-Pro-Hyp-Gly-Cha-Ser-Pro-Leu) in B1R-positive (B1R+) HEK293T::hB1R tumor xenografts in mice. In this study, we compare (68)Ga-P03034 with (68)Ga-labeled P04158 ((68)Ga-DOTA-dPEG2-Lys-Lys-Arg-Pro-Hyp-Gly-Igl-Ser-D-Igl-Oic) and Z02090 ((68)Ga-DOTA-dPEG2-Lys-Lys-Arg-Pro-Hyp-Gly-Cpg-Ser-D-Tic-Cpg) derived from 2 potent B1R antagonists, B9858 and B9958, respectively, for imaging B1R expression with PET.

METHODS

Peptide sequences were assembled on solid-phase. Cold standards were prepared by incubating DOTA-conjugated peptides with GaCl3. Binding affinity was measured via competition binding assays using hB1R-expressing Chinese hamster ovary-K1 cell membranes. (68)Ga labeling was performed in N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) buffer with microwave heating and purified by high-performance liquid chromatography. Imaging/biodistribution studies were performed in mice bearing wild-type HEK293T (B1R-) and B1R+ HEK293T::hB1R tumors.

RESULTS

P03034, P04158, and Z02090 bound B1R with high affinity, with Ki values at 16.0 ± 2.9, 1.5 ± 1.9, and 1.1 ± 0.8 nM, respectively. (68)Ga-labeled P03034, P04159, and Z02090 were obtained in greater than 50% decay-corrected radiochemical yields with more than 99% radiochemical purity. Biodistribution studies showed that all three (68)Ga-labeled tracers cleared rapidly from the blood and normal tissues, with excretion mainly via the renal pathway. At 1 h after injection, only the kidneys, bladders, and B1R+ HEK293T::hB1R tumors were clearly visualized in PET images. Uptake values of (68)Ga-labeled P03034, P04158, and Z02090 in B1R+ tumors were 2.17 ± 0.49, 19.6 ± 4.50, and 14.4 ± 1.63 percentage injected dose per gram, respectively. Uptake ratios of B1R+ to B1R- tumor, blood, and muscle were 6.23 ± 1.69, 5.72 ± 2.20, and 25.5 ± 13.1 for (68)Ga-P03034; 34.5 ± 10.5, 19.2 ± 8.21, and 66.1 ± 17.0 for (68)Ga-P04158; and 29.3 ± 9.68, 29.9 ± 5.58, and 124 ± 28.1 for (68)Ga-Z02090, respectively.

CONCLUSION

All three (68)Ga-labeled B1R-targeting peptides generated specific and high-contrasted images of B1R+ tumors xenografted in mice. With significantly higher tumor uptake and target-to-nontarget ratios, (68)Ga-labeled P04158 and Z02090 are superior to P03034 for imaging B1R expression with PET.

摘要

未标记

缓激肽B1受体(B1R)是一种G蛋白偶联受体,在多种癌症中过度表达。B1R在健康组织中不表达,这使其成为一种有吸引力的癌症成像标志物。此前,我们报道了(68)Ga-P03034((68)Ga-DOTA-dPEG2-Lys-Arg-Pro-Hyp-Gly-Cha-Ser-Pro-Leu)在B1R阳性(B1R+)HEK293T::hB1R小鼠肿瘤异种移植模型中的选择性摄取。在本研究中,我们将(68)Ga-P03034与分别源自两种强效B1R拮抗剂B9858和B9958的(68)Ga标记的P04158((68)Ga-DOTA-dPEG2-Lys-Lys-Arg-Pro-Hyp-Gly-Igl-Ser-D-Igl-Oic)和Z020进行比较,用于通过PET成像B1R表达。

方法

肽序列在固相上组装。通过将DOTA缀合的肽与GaCl3孵育制备冷标准品。使用表达hB1R的中国仓鼠卵巢-K1细胞膜通过竞争结合试验测量结合亲和力。在N-(2-羟乙基)哌嗪-N'-(2-乙磺酸)缓冲液中通过微波加热进行(68)Ga标记,并通过高效液相色谱法纯化。在携带野生型HEK293T(B1R-)和B1R+ HEK293T::hB1R肿瘤的小鼠中进行成像/生物分布研究。

结果

P03034、P04158和Z02090与B1R具有高亲和力结合,Ki值分别为16.0±2.9、1.5±1.9和1.1±0.8 nM。(68)Ga标记的P03034、P04159和Z02090的衰变校正放射化学产率大于50%,放射化学纯度大于99%。生物分布研究表明,所有三种(68)Ga标记的示踪剂均从血液和正常组织中快速清除,排泄主要通过肾脏途径。注射后1小时,在PET图像中仅肾脏、膀胱和B1R+ HEK293T::hB1R肿瘤清晰可见。(68)Ga标记的P03034、P04158和Z02090在B1R+肿瘤中的摄取值分别为每克注射剂量的2.17±0.49、19.6±4.50和14.4±1.63百分比。(68)Ga-P03034的B1R+与B1R-肿瘤、血液和肌肉的摄取比分别为6.23±1.69、5.72±2.20和25.5±13.1;(68)Ga-P04158的分别为34.5±10.5、19.2±8.21和66.1±17.0;(68)Ga-Z02090的分别为29.3±9.68、29.9±5.58和124±。

结论

所有三种(68)Ga标记的靶向B1R的肽在小鼠中产生了B1R+肿瘤异种移植的特异性和高对比度图像。(68)Ga标记的P04158和Z02090具有显著更高的肿瘤摄取和靶非靶比,在通过PET成像B1R表达方面优于P03034。

文献AI研究员

20分钟写一篇综述,助力文献阅读效率提升50倍。

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索

文档翻译

学术文献翻译模型,支持多种主流文档格式。

立即体验