Comparative study of 64Cu/NOTA-[D-Tyr6,βAla11,Thi13,Nle14]BBN(6-14) monomer and dimers for prostate cancer PET imaging.
Comparative study of 64Cu/NOTA-[D-Tyr6,βAla11,Thi13,Nle14]BBN(6-14) monomer and dimers for prostate cancer PET imaging.
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DOI：
10.1186/2191-219x-2-8
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发表时间：
2012-02-14
期刊：
影响因子：
3.2
通讯作者：
Guérin B
中科院分区：
文献类型：
--
作者：
Fournier P;Dumulon-Perreault V;Ait-Mohand S;Langlois R;Bénard F;Lecomte R;Guérin B
胃泌素释放肽受体[GRPR]在多种癌症中高度过度表达，已被研究作为诊断靶点。多聚体胃泌素释放肽有望增强肿瘤对GRPR的摄取和亲和力。本研究比较了1，4，7-三氮杂环烷-1，4，7-三乙酸二聚体和[D-Tyr6，β-Ala11，Thi13，Nle14]蛙黄素(6-14)[BBN(6-14)]的两个二聚体。在固相载体上合成了单体和二聚体多肽，并用~(64)Cu进行放射性标记。NOTA-二聚体1由不对称连接的BBN(6-14)组成，而NOTA-二聚体2在两个BBN(6-14)配体和螯合剂之间具有相似的间隔基。体外竞争结合实验测定PC3人前列腺癌细胞与GRPR的结合亲和力。在Balb/c小鼠体内评价了放射性标记化合物的稳定性和生物分布。用放射性标记的NOTA单体和NOTA-二聚体2对PC3细胞进行持续4h的摄取和外排检测，用μ正电子发射计算机断层扫描(μ)显像检测荷瘤裸鼠体内的生物分布动力学，并经解剖和计数证实。制备了NOTA单体、NOTA二聚体1和NOTA二聚体2，纯度为99%。三种BBN多肽的抑制常数相当，且在低纳摩尔范围内。所有64Cu标记的多肽在小鼠血浆中稳定到24小时，在体内稳定到1小时。与64Cu/NOTA-二聚体1相比，64Cu/NOTA-二聚体2具有更长的两个BBN(6-14)配体之间的间隔，是一种更有效的GRPR靶向探针。与64Cu/NOTA-二聚体2相比，64Cu/NOTA-二聚体2的PC3肿瘤摄取谱略有不同；与64Cu/NOTA-二聚体2相比，单体BBN-多肽示踪剂在第一个0.5h内显示出更高的肿瘤摄取率和快速的肾脏清除，从而导致更高的肿瘤肌肉比。与64Cu/NOTA-二聚体2相比，64Cu/NOTA-二聚体2具有更高的肿瘤与血液的比率，并且在肿瘤部位停留的时间更长。阻断实验中肿瘤与血液和肿瘤与肌肉的比率较低，表明这两种示踪剂对肿瘤的摄取都依赖于GRPR。~(64)Cu/NOTA-单体和~(64)Cu/NOTA-二聚体2均适用于体内GRPR阳性前列腺癌的PET检测。通过应用多价效应和/或统计重新结合，64Cu/NOTA-二聚体2在体内改善了肿瘤滞留。
Gastrin-releasing peptide receptors [GRPR] are highly over-expressed in multiple cancers and have been studied as a diagnostic target. Multimeric gastrin-releasing peptides are expected to have enhanced tumor uptake and affinity for GRPR. In this study, a 64Cu-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid [NOTA]-monomer and two NOTA-dimers of [D-Tyr6,βAla11, Thi13, Nle14]bombesin(6-14) ] [BBN(6-14)] were compared. Monomeric and dimeric peptides were synthesized on solid phase support and radiolabeled with 64Cu. NOTA-dimer 1 consists of asymmetrically linked BBN(6-14), while NOTA-dimer 2 has similar spacer between the two BBN(6-14) ligands and the chelator. In vitro GRPR-binding affinities were determined with competitive binding assays on PC3 human prostate cancer cells. In vivo stability and biodistribution of radiolabeled compounds were assessed in Balb/c mice. Cellular uptake and efflux were measured with radiolabeled NOTA-monomer and NOTA-dimer 2 on PC3 cells for up to 4 h. In vivo biodistribution kinetics were measured in PC3 tumor-bearing Balb/c nude mice by μ-positron emission tomography [μPET] imaging and confirmed by dissection and counting. NOTA-monomer, NOTA-dimers 1 and 2 were prepared with purity of 99%. The inhibition constants of the three BBN peptides were comparable and in the low nanomolar range. All 64Cu-labeled peptides were stable up to 24 h in mouse plasma and 1 h in vivo. 64Cu/NOTA-dimer 2 featuring a longer spacer between the two BBN(6-14) ligands is a more potent GRPR-targeting probe than 64Cu/NOTA-dimer 1. PC3 tumor uptake profiles are slightly different for 64Cu/NOTA-monomer and 64Cu/NOTA-dimer 2; the monomeric BBN-peptide tracer exhibited higher tumor uptake during the first 0.5 h and a fast renal clearance resulting in higher tumor-to-muscle ratio when compared to 64Cu/NOTA-dimer 2. The latter exhibited higher tumor-to-blood ratio and was retained longer at the tumor site when compared to 64Cu/NOTA-monomer. Lower ratios of tumor-to-blood and tumor-to-muscle in blocking experiments showed GRPR-dependant tumor uptake for both tracers. Both 64Cu/NOTA-monomer and 64Cu/NOTA-dimer 2 are suitable for detecting GRPR-positive prostate cancer in vivo by PET. Tumor retention was improved in vivo with 64Cu/NOTA-dimer 2 by applying polyvalency effect and/or statistical rebinding.