Department of Nuclear Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia.
J Med Chem. 2011 Apr 28;54(8):2602-9. doi: 10.1021/jm101279a. Epub 2011 Apr 1.
The development of metabolically stable radiolabeled gastrin analogues with suitable pharmacokinetics is a topic of recent research activity. These imaging vectors are of interest because the gastrin/CCK2 receptor is highly overexpressed in different tumors such as medullary thyroid cancer, neuroendocrine tumors, and SCLC. The drawback of current targeting agents is either their metabolic instability or their high kidney uptake. We present the synthesis and in vitro and in vivo evaluation of 11 (111)In-labeled DOTA-conjugated peptides that differ by their spacer between the peptide and the chelate. We introduced uncharged but hydrophilic spacers such as oligoethyleneglycol, serine, and glutamine. The affinity of all radiopeptides was high with IC(50) values between 0.5 and 4.8 nM. The improvement of human serum stability is 500-fold within this series of compounds. In addition the kidney uptake could be lowered distinctly and the tumor-to-kidney ratio improved almost 60-fold if compared with radiotracers having charged spacers such as glutamic acid.
具有合适药代动力学的代谢稳定放射性标记胃泌素类似物的开发是近期研究活动的一个主题。这些成像载体很有意义，因为胃泌素/CCK2 受体在不同的肿瘤中高度过表达，如甲状腺髓样癌、神经内分泌肿瘤和小细胞肺癌。目前靶向剂的缺点是代谢不稳定或肾脏摄取高。我们介绍了 11（111）In 标记的 DOTA 缀合肽的合成及体外和体内评价，这些肽在肽和螯合剂之间的间隔有所不同。我们引入了不带电荷但亲水性的间隔物，如聚乙二醇、丝氨酸和谷氨酰胺。所有放射性肽的亲和力都很高，IC（50）值在 0.5 和 4.8 nM 之间。在这一系列化合物中，人血清稳定性提高了 500 倍。此外，如果与带电荷间隔物（如谷氨酸）的放射性示踪剂相比，肾脏摄取可明显降低，肿瘤与肾脏的比值可提高近 60 倍。
