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

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

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

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-DBCO-Y3- TATE (AP) and CB-TE1K1P-PEG4-DBCO-Y3-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 Kd 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.

Original languageEnglish (US)
Pages (from-to)6019-6029
Number of pages11
JournalJournal of Medicinal Chemistry
Volume57
Issue number14
DOIs
StatePublished - Jul 24 2014

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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