Stereochemistry of Amino Acid Spacers Determines the Pharmacokinetics of 111In鈥揇OTA鈥揗inigastrin Analogues for Targeting the CCK2/Gastrin Receptor

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• 作者：Petra Kolenc Peitl ; MariaLuisa Tamma ; Marko Kroselj ; Friederike Braun ; Beatrice Waser ; Jean Claude Reubi ; Marija Sollner Dolenc ; Helmut R. Maecke ; Rosalba Mansi
• 刊名：Bioconjugate Chemistry
• 出版年：2015
• 出版时间：June 17, 2015
• 年：2015
• 卷：26
• 期：6
• 页码：1113-1119
• 全文大小：265K
• ISSN：1520-4812

文摘

The metabolic instability and high kidney retention of minigastrin (MG) analogues hamper their suitability for use in peptide鈥搑eceptor radionuclide therapy of CCK2/gastrin receptor-expressing tumors. High kidney retention has been related to N-terminal glutamic acids and can be substantially reduced by coinjection of polyglutamic acids or gelofusine. The aim of the present study was to investigate the influence of the stereochemistry of the N-terminal amino acid spacer on the enzymatic stability and pharmacokinetics of ¹¹¹In鈥揇OTA鈥?d-Glu)₆-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH₂ (¹¹¹In鈥揚P11鈥?b>D) and ¹¹¹In鈥揇OTA鈥?l-Glu)₆-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH₂ (¹¹¹In鈥揚P11鈥?b>L). Using circular dichroism measurements, we demonstrate the important role of secondary structure on the pharmacokinetics of the two MG analogues. The higher in vitro serum stability together with the improved tumor-to-kidney ratio of the (d-Glu)₆ congener indicates that this MG analogue might be a good candidate for further clinical study.