Division of Radiological Chemistry, University Hospital Basel, Switzerland.
Eur J Nucl Med Mol Imaging. 2012 Dec;39(12):1876-85. doi: 10.1007/s00259-012-2231-8. Epub 2012 Aug 29.
Targeting of tumours positive for somatostatin receptors (sst) with radiolabelled peptides is of interest for tumour localization, staging, therapy follow-up and targeted radionuclide therapy. The peptides used clinically are exclusively agonists, but recently we have shown that the radiolabelled somatostatin-based antagonist (111)In-DOTA-sst2-ANT may be preferable to agonists. However, a comprehensive study of this radiolabelled antagonist to determine its significance was lacking. The present report describes the evaluation of this novel antagonist labelled with (111)In and (177)Lu in three different tumour models.
Radiopeptide binding, internalization and dissociation studies were performed using cells expressing HEK293-rsst(2). Biodistribution studies were performed in HEK293-rsst(2), HEK293-hsst(2) and HEK293-rsst(3) xenografted mice.
Saturation binding analysis confirmed earlier IC(50) data for (111/nat)In-DOTA-sst2-ANT and showed similar affinity of (177/nat)Lu-DOTA-sst2-ANT for the sst(2). Only low internalization was found in cell culture (6.68 ± 0.06 % at 4 h), which was not unexpected for an antagonist, and this could be further reduced by the addition of sucrose. No internalization was observed in HEK293 cells not expressing sst. Both results indicate that the internalization was specific. (111)In-DOTA-sst2-ANT and (177)Lu-DOTA-sst2-ANT were shown to target tumour xenografts expressing the rat and the human sst(2) receptor with no differences in their uptake or pharmacokinetics. The uptake in rsst(2) and hsst(2) was high (about 30 %IA/g 4 h after injection) and surprisingly long-lasting (about 20-23 %IA/g 24 h after injection). Kidney uptake was blocked by approximately 50 % by lysine or Gelofusine.
These results indicate that radiolabelled somatostatin-based antagonists may be superior to corresponding agonists. The long tumour retention time of (177)Lu-DOTA-sst2-ANT indicates that this new class of compounds is of relevance not only in diagnostic imaging but also in targeted radionuclide therapy of sst-positive tumours.
用放射性标记肽靶向生长抑素受体（sst）阳性肿瘤，对肿瘤定位、分期、治疗随访和靶向放射性核素治疗具有重要意义。临床上使用的肽仅为激动剂，但最近我们发现放射性标记的基于生长抑素的拮抗剂（111）In-DOTA-sst2-ANT 可能优于激动剂。然而，缺乏对这种放射性标记拮抗剂的全面研究来确定其意义。本报告描述了用（111）In 和（177）Lu 标记这种新型拮抗剂在三种不同肿瘤模型中的评估。
使用表达 HEK293-rsst（2）的细胞进行放射性肽结合、内化和解离研究。在 HEK293-rsst（2）、HEK293-hsst（2）和 HEK293-rsst（3）异种移植小鼠中进行了生物分布研究。
饱和结合分析证实了（111/nat）In-DOTA-sst2-ANT 的早期 IC（50）数据，并显示（177/nat）Lu-DOTA-sst2-ANT 对 sst（2）的亲和力相似。在细胞培养中仅发现低内化（4 h 时为 6.68±0.06%），这对于拮抗剂来说并不意外，并且通过添加蔗糖可以进一步降低内化。在不表达 sst 的 HEK293 细胞中未观察到内化。这两个结果都表明内化是特异性的。（111）In-DOTA-sst2-ANT 和（177）Lu-DOTA-sst2-ANT 被证明可以靶向表达大鼠和人 sst（2）受体的肿瘤异种移植物，其摄取或药代动力学没有差异。在 rsst（2）和 hsst（2）中的摄取量很高（注射后 4 h 约为 30%IA/g），并且持续时间非常长（注射后 24 h 约为 20-23%IA/g）。通过赖氨酸或 Gelofusine 可将肾脏摄取量阻断约 50%。
这些结果表明，放射性标记的基于生长抑素的拮抗剂可能优于相应的激动剂。（177）Lu-DOTA-sst2-ANT 的长肿瘤保留时间表明，这种新型化合物不仅在诊断成像中具有重要意义，而且在治疗 sst 阳性肿瘤的靶向放射性核素治疗中也具有重要意义。
