Synthesis of a New Heterobifunctional Linker, N-[4-(Aminooxy)butyl]maleimide, for Facile Access to a Thiol-Reactive 18F-Labeling Agent

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• 作者：Tatsushi Toyokuni ; Joseph C. Walsh ; Alan Dominguez ; Michael E. Phelps ; Jorge R. Barrio ; Sanjiv S. Gambhir ; and Nagichettiar Satyamurthy
• 刊名：Bioconjugate Chemistry
• 出版年：2003
• 出版时间：November 2003
• 年：2003
• 卷：14
• 期：6
• 页码：1253 - 1259
• 全文大小：114K
• 年卷期：v.14,no.6(November 2003)
• ISSN：1520-4812

文摘

A new heterobifunctional linker containing an aldehyde-reactive aminooxy group and a thiol-reactivemaleimide group, namely N-[4-(aminooxy)butyl]maleimide, was synthesized as a stable HCl salt byO-alkylation of either N-hydroxyphthalimide or N-(4-monomethoxytrityl)hydroxylamine, followed byN-alkylation of maleimide, in an overall yield of 18% (seven steps) or 29% (five steps), respectively.This heterobifunctional linker allowed a simple and efficient synthesis of a maleimide-containing thiol-reactive ¹⁸F-labeling agent. Thus, N-{4-[(4-[¹⁸F]fluorobenzylidene)aminooxy]butyl}maleimide (specificactivity: ~3000 Ci/mmol at end of synthesis) was synthesized in two steps involving the preparationof 4-[¹⁸F]fluorobenzaldehyde, followed by its aminooxy-aldehyde coupling reaction to the heterobifunctional linker, with an overall radiochemical yield of ~35% (decay corrected) within ~60 min fromend of bombardment. Initial ¹⁸F-labeling experiments were carried out using a thiol-containingtripeptide glutathione (GSH) and a 5'-thiol-functionalized oligodeoxynucleotide (5'-S-ODN) inphosphate-buffered saline (PBS, pH 7.5). After standing at room temperature for 10 min, the ¹⁸F-labeled GSH and 5'-S-ODN were obtained in ¹⁸F-labeling yields of ~70% and ~5% (decay-corrected),respectively. The heterobifunctional linker is easy to synthesize and provides a facile access to themaleimide-containing thiol-reactive ¹⁸F-labeling agent, which could be advantageously employed inthe development of ¹⁸F-labeled biomomolecules for use with positron emission tomography.