64Cu-Labeled Somatostatin Analogues Conjugated with Cross-Bridged Phosphonate-Based Chelators via Strain-Promoted Click Chemistry for PET Imaging: In silico through in Vivo Studies

详细信息    查看全文

• 作者：Zhengxin Cai ; Qin Ouyang ; Dexing Zeng ; Kim N. Nguyen ; Jalpa Modi ; Lirong Wang ; Alexander G. White ; Buck E. Rogers ; Xiang-Qun Xie ; Carolyn J. Anderson
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：July 24, 2014
• 年：2014
• 卷：57
• 期：14
• 页码：6019-6029
• 全文大小：587K
• ISSN：1520-4804

文摘

Somatostatin receptor subtype 2 (sstr2) is a G-protein-coupled receptor (GPCR) that is overexpressed in neuroendocrine tumors. The homology model of sstr2 was built and was used to aid the design of new somatostatin analogues modified with phosphonate-containing cross-bridged chelators for evaluation of using them as PET imaging radiopharmaceuticals. The new generation chelators were conjugated to Tyr³-octreotate (Y3-TATE) through bioorthogonal, strain-promoted alkyne azide cycloaddition (SPAAC) to form CB-TE1A1P鈥揇BCO鈥揧3-TATE (AP) and CB-TE1K1P鈥揚EG4鈥揇BCO鈥揧3-TATE (KP) in improved yields compared to standard direct conjugation methods of amide bond formation. Consistent with docking studies, the clicked bioconjugates showed high binding affinities to sstr2, with K_d values ranging from 0.6 to 2.3 nM. Selected isomers of the clicked products were used in biodistribution and PET/CT imaging. Introduction of the bulky dibenzocyclooctyne group in AP decreased clearance rates from circulation. However, the additional carboxylate group and PEG linker from the KP conjugate significantly improved labeling conditions and in vivo stability of the copper complex and ameliorated the slower pharmacokinetics of the clicked somatostatin analogues.