[99mTc]Demobesin 1, a novel potent bombesin analogue for GRP receptor-targeted tumour imaging
[99mTc]Demobesin 1, a novel potent bombesin analogue for GRP receptor-targeted tumour imaging
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DOI：
10.1007/s00259-002-1040-x
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发表时间：
2003-02-01
影响因子：
9.1
通讯作者：
Maina, T
中科院分区：
文献类型：
--
作者：
Nock, B;Nikolopoulou, A;Maina, T
Demobesin-1是一种有效的新的GRP-R选择性蛙皮素(BN)类似物，它含有一个开链的四胺螯合剂，可以稳定地与~(99m)Tm结合。在一种方便的标记方法之后，放射性多肽[TC-99m]Demobesin 1以几乎定量的产率和高的比活性形成。在人雄激素非依赖性前列腺癌PC-3细胞系的膜制剂中，未标记和标记的多肽均显示高亲和力结合。测得Demobesin 1和[Tyro]BN的IC50值分别为0.70+/-0.08 nM和1.5+/-0.20 nM，[TC-99m/TC-99g]Demobesin 1的K-d为0.67+/-0.10 nM。[TC-99m]Demobesin 1在小鼠血浆中较稳定，在肾脏和肝脏匀浆中降解较快。体内受体阻断实验表明，[TC-99m]Demobesin 1注射在健康的瑞士白化小鼠体内后，通过GRP-R介导的过程在靶器官(胰腺、肠道)中非常有效地积聚。[TC-99m]Demobesin 1在PC-3荷瘤裸鼠体内表现出同样高的摄取和GRP-R介导的摄取。在PC-3移植瘤中，初始高摄取率为16.2+/-3.1%ID/g。在4h P.I.时保持在相似的水平(15.61+/-1.19%ID/g)。即使在24小时后，当放射性从所有其他组织中清除时，肿瘤中仍观察到5.24+/-0.67%ID/g的值。[TC-99m]Demobesin 1在肿瘤部位的高定位和长时间定位，以及其快速的背景清除，是GRP-R靶向肿瘤成像的非常有前途的特性。
Demobesin 1 is a potent new GRP-R-selective bombesin (BN) analogue containing an open chain tetraamine chelator for stable technetium-99m binding. Following a convenient labelling protocol, the radiopeptide, [Tc-99m]Demobesin 1, formed in nearly quantitative yields and with high specific activities. Both unlabelled and labelled peptide demonstrated high-affinity binding in membrane preparations of the human androgen-independent prostate adenocarcinoma PC-3 cell line. The IC50 values determined for Demobesin 1 and [Tyro]BN were 0.70+/-0.08 nM and 1.5+/-0.20 nM, respectively, while the K-d defined for [Tc-99m/Tc-99g]Demobesin 1 was 0.67+/-0.10 nM. [Tc-99m]Demobesin 1 was rather stable in murine plasma, whereas it degraded rapidly in kidney and liver homogenates. After injection in healthy Swiss albino mice, [Tc-99m]Demobesin 1 accumulated very efficiently in the target organs (pancreas, intestinal tract) via a GRP-R-mediated process, as shown by in vivo receptor blocking experiments. An equally high and GRP-R-mediated uptake was exhibited by [Tc-99m]Demobesin 1 after injection in PC-3 tumour-bearing athymic mice. The initial high radioligand uptake of 16.2+/-3.1%ID/g in the PC-3 xenografts at 1 h p.i. remained at a similar level (15.61+/-1.19%ID/g) at 4 h p.i. Even after 24 h p.i., when the radioactivity had cleared from all other tissues, a value of 5.24+/-0.67%ID/g was still observed in the tumour. The high and prolonged localization of [Tc-99m]Demobesin 1 at the tumour site and its rapid background clearance are very promising qualities for GRP-R-targeted tumour imaging in man.