Synthesis and preclinical characterization of [⁶⁴Cu]NODAGA-MAL-exendin-4 with a N^蔚-maleoyl-l-lysyl-glycine linkage

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• 作者：Cheng-Bin Yim ; Kirsi Mikkola ; Veronica Fagerholm ; Viki-Veikko Elomaa ; Tamiko Ishizu ; Johan Raj ; er ; Joern Schlesinger ; Anne Roivainen ; Pirjo Nuutila ; Olof Solin
• 关键词：Copper-64 ; Exendin ; GLP-1 receptor ; NODAGA ; Renal brush border membrane
• 刊名：Nuclear Medicine and Biology
• 出版年：November, 2013
• 年：2013
• 卷：40
• 期：8
• 页码：1006-1012
• 全文大小：1153 K

文摘

Introduction

Renal localization of high radioactivity levels during targeted imaging compromises tissue visualization in the kidney region and limits diagnostic accuracy. Radioiodinated antibody fragments with a renal enzyme-cleavable N^蔚-maleoyl-l-lysyl-glycine (MAL) linkage demonstrated low renal radioactivity levels in mice, from early postinjection times. This study tested the hypothesis whether a ⁶⁴Cu-labeled NODAGA-exendin-4 peptide with a MAL linkage ([⁶⁴Cu]NODAGA-MAL-exendin-4) could decrease kidney radioactivity levels in rats, compared to a [⁶⁴Cu]NODAGA-exendin-4 reference, without impairing the radioactivity levels in the target tissue.

Methods

NODAGA-MAL-exendin-4 was synthesized in a two-phase approach using solid support to prepare maleoyl-derivatized NODAGA followed by Michael addition to cysteine-derivatized exendin-4 in solution. Radiolabeling was performed in buffered aqua with [⁶⁴Cu]CuCl₂, which was produced via the ⁶⁴Ni(p,n)⁶⁴Cu nuclear reaction. The in vitro and in vivo stability, lipophilicity, and distribution kinetics in major rat organs for [⁶⁴Cu]NODAGA-MAL-exendin-4 were studied and compared to [⁶⁴Cu]NODAGA-exendin-4. Labeling of pancreatic islets was assessed using autoradiography.

Results

NODAGA-MAL-exendin-4 was synthesized, with an overall yield of 9%, and radiolabeled with ⁶⁴Cu with high specific radioactivity. Serum incubation studies showed high stability for [⁶⁴Cu]NODAGA-MAL-exendin-4. Similar tissue distribution kinetics was observed for [⁶⁴Cu]NODAGA-MAL-exendin-4 and [⁶⁴Cu]NODAGA-exendin-4, with high kidney radioactivity levels.

Conclusions

The incorporated MAL linkage in [⁶⁴Cu]NODAGA-MAL-exendin-4 was unable to reduce kidney radioactivity levels, compared to [⁶⁴Cu]NODAGA-exendin-4. The applicability of metabolizable linkages in the design of kidney-saving exendin-4 analogs requires further investigation.