锝[99mTc]标记胰岛素的合成与表征。

Synthesis and characterization of rhenium and technetium-99m labeled insulin.

机构信息

Departments of Chemistry and Medical Physics & Applied Radiation Sciences, McMaster University, Hamilton, Ontario L8S 4M1, Canada.

出版信息

J Med Chem. 2010 Mar 25;53(6):2612-21. doi: 10.1021/jm100096c.

DOI:10.1021/jm100096c

PMID:20235598

Abstract

A (99m)Tc-labeled insulin analogue was synthesized through a direct labeling method in which the (99m)Tc(CO)(3) core was combined with a protected insulin derivative (9) bearing a M(I) chelate linked to the first amino acid of the B-chain (B1). Regioselective labeling was achieved by careful control over the pH and the reaction time. Following a TFA-anisole mediated deprotection step (decay-corrected yield of 30 +/- 11%, n = 4), the identity of the final (99m)Tc-labeled product was confirmed by HPLC. Displacement of (125)I-insulin from the insulin receptor (IR) by the Re analogue 6 was similar to that of native insulin (17.8 nM vs 11.7 nM, respectively). The extent of autophosphorylation and Akt activation, as indicated by production of phospho-Akt (pAkt), showed no statistical difference between 6 and native insulin in both assays. These results support the use of the reported (99m)Tc-insulin derivative as a tracer for studying insulin biochemistry in vivo.

摘要

一种（99m）Tc 标记的胰岛素类似物通过直接标记方法合成，其中 (99m)Tc(CO)(3) 核心与带有 M(I)螯合物的保护胰岛素衍生物（9）结合，该螯合物连接到 B 链的第一个氨基酸（B1）。通过仔细控制 pH 值和反应时间，可以实现区域选择性标记。在 TFA-茴香醚介导的脱保护步骤（校正后衰减的产率为 30 +/- 11%，n = 4）后，通过 HPLC 确认了最终（99m）Tc 标记产物的身份。Re 类似物 6 从胰岛素受体（IR）置换（125）I-胰岛素的能力与天然胰岛素相似（分别为 17.8 nM 和 11.7 nM）。在两种测定中，6 和天然胰岛素的自动磷酸化和 Akt 激活程度（如磷酸化 Akt（pAkt）的产生所示）没有统计学差异。这些结果支持使用报道的（99m）Tc 胰岛素衍生物作为示踪剂来研究体内胰岛素生物化学。