不断探索几种HER2特异性肽，以寻找具有适当药代动力学特性的候选肽，以便开发有效的放射性药物，并可应用于对乳腺癌患者进行临床筛查。在本研究中，我们改进了我们先前报道的[177Lu]DOTA-L-A9肽，旨在制备具有改善代谢稳定性和体内药代动力学性能的放射性肽。我们设计了一个全为d-氨基酸的“反序”肽和一个“反-反序”肽，其中d-氨基酸的顺序被颠倒。通过圆二色谱研究，与“反序”A9肽相比，“反-反序”A9变体表现出更高的二级结构稳定性。两种放射性肽[177Lu]DOTA-D-A9和[177Lu]DOTA-rD-A9相较原始的l-肽，在体内代谢稳定性上有明显改善。“反-反序”变体[177Lu]DOTA-rD-A9与“反序”肽[177Lu]DOTA-D-A9和原始肽[177Lu]DOTA-L-A9相比，显示出更好的药代动力学行为，并具有明显更高的肿瘤摄取率。在A9肽的情况下，d-氨基酸的肽序列颠倒提高了HER2阳性肿瘤中放射性物质的摄取和保留。本研究可为肽的设计和开发提供指导，以制备更新和改进的肽版本。版权所有 © 2023 Elsevier Inc. 保留所有权利。

Several HER2-specific peptides are being continuously explored to find a candidate with suitable pharmacokinetic properties for development of effective radiopharmaceutical that can find applications for clinical screening of breast cancer patients. In the present work with an aim of preparing a radiopeptide with improved metabolic stability and in vivo pharmacokinetic performance we modified our previously reported [177Lu]DOTA-L-A9 peptide. Here we designed an 'inverso' peptide with all d-amino acids and a 'retro-inverso' peptide where sequence of d-amino acids was reversed. Higher secondary structure stabilization of retro- inverso A9 variant compared to inverso A9 peptide was evident by circular dichroism studies. The two radiopeptides [177Lu]DOTA-D-A9 and [177Lu]DOTA-rD-A9 exhibited significantly improved in vivo metabolic stability over the original l-peptide. The retro-inverso variant, [177Lu]DOTA-rD-A9 demonstrated better pharmacokinetic behavior with significantly higher tumor uptake than the inverso peptide, [177Lu]DOTA-D-A9 and the original peptide, [177Lu]DOTA-L-A9. In the present case of A9 peptide, reversal of the peptide sequence of d-amino acids boosted the uptake and retention of radioactivity in HER2-positive tumor. The present study can thus guide the design and development of newer and improved versions of peptides.Copyright © 2023 Elsevier Inc. All rights reserved.