Convergent synthesis of 13N-labelled Peptidic structures using aqueous [13N]NH3
Convergent synthesis of 13N-labelled Peptidic structures using aqueous [13N]NH3
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DOI：
10.1186/s41181-017-0035-7
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发表时间：
2017-12-19
影响因子：
4.6
通讯作者：
Gee, Antony D.
中科院分区：
文献类型：
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作者：
Blower, Julia E.;Cousin, Samuel F.;Gee, Antony D.
背景氮-13具有10分钟的半衰期，这对将其掺入PET成像剂的可行合成方法的复杂性施加了时间限制。在探索克服这种限制的方法时，我们使用Ugi反应开发了一种快速的一锅法，用于使用[N-13]NH3作为合成前体放射性标记肽分子。方法将加入载体的[N-13]NH3（50 μ L）加入到羧酸、醛和异氰化物的2，2，2-TFE（200 μ L）溶液中。将混合物在微波合成器中于120 ℃加热10 min。通过放射性HPLC和放射性LCMS分析反应。如Ugi 1所示，通过半制备型放射性HPLC分离目标N-13标记的肽Ugi化合物。结果各反应的放射性HPLC分析证实了与其各自的参比标准品共洗脱的放射性产物的形成，粗产物的放射化学产率范围为11%至23%。两个环状γ-内酰胺结构也通过分子内反应实现。在放射性色谱图中观察到的其他放射性副产物被鉴别为[N-13]NH3与两个异氰化物分子反应形成的N-13标记的二亚胺。使用半制备型HPLC分离所需的N-13标记的Ugi产物。结论我们开发了一种以[N-13]NH3水溶液为合成前体，用N-13放射性标记复合肽分子的一锅法。
Background Nitrogen-13 has a 10-min half-life which places time constraints on the complexity of viable synthetic methods for its incorporation into PET imaging agents. In exploring ways to overcome this limitation, we have used the Ugi reaction to develop a rapid one-pot method for radiolabelling peptidic molecules using [N-13]NH3 as a synthetic precursor. Methods Carrier-added [N-13]NH3 (50 mu L) was added to a solution of carboxylic acid, aldehyde, and isocyanide in 2,2,2-TFE (200 mu L). The mixture was heated in a microwave synthesiser at 120 degrees C for 10 min. Reactions were analysed by radio-HPLC and radio-LCMS. Isolation of the target N-13-labelled peptidic Ugi compound was achieved via semi-preparative radio-HPLC as demonstrated for Ugi1. Results Radio-HPLC analysis of each reaction confirmed the formation of radioactive products co-eluting with their respective reference standards with radiochemical yields of the crude products ranging from 11% to 23%. Two cyclic gamma-lactam structures were also achieved via intra-molecular reactions. Additional radioactive by-products observed in the radio-chromatogram were identified as N-13-labelled di-imines formed from the reaction of [N-13]NH3 with two isocyanide molecules. The desired N-13-labelled Ugi product was isolated using semi-preparative HPLC. Conclusion We have developed a one-pot method that opens up new routes to radiolabel complex, peptidic molecules with N-13 using aqueous [N-13]NH3 as a synthetic precursor.