Synthesis and opioid receptor binding of indium (III) and [111In]-labeled macrocyclic conjugates of diprenorphine: novel ligands designed for imaging studies of peripheral opioid receptors

Shefali Srivastava, Emily A. Fergason-Cantrell, Roger I. Nahas, John R. Lever

Research output: Contribution to journalArticle

Abstract

Radiolabeled diprenorphine (DPN) and analogs are widely used ligands for non-invasive brain imaging of opioid receptors. To develop complementary radioligands optimized for studies of the peripheral opioid receptors, we prepared a pair of hydrophilic DPN derivatives, conjugated to the macrocyclic chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), for complexation with trivalent metals. The non-radioactive indium (III) complexes, tethered to the C6-oxygen position of the DPN scaffold by 6- to 9-atom spacers, displayed high affinities for binding to μ, δ and κ opioid receptors in vitro. Use of the 9-atom linker conferred picomolar affinities equipotent to those of the parent ligand DPN. The [111In]-labeled complexes were prepared in good yield (>70%), with high radiochemical purity (∼99%) and high specific radioactivity (>4000 mCi/μmol). Their log D7.4 values were –2.21 to –1.66. In comparison, DPN is lipophilic, with a log D7.4 of +2.25. Further study in vivo is warranted to assess the suitability of these [111In]-labeled DPN-DOTA conjugates for imaging trials.

Original languageEnglish (US)
Pages (from-to)6127-6135
Number of pages9
JournalTetrahedron
Volume72
Issue number40
DOIs
StatePublished - Oct 6 2016
Externally publishedYes

Keywords

  • Bioconjugate
  • Diprenorphine
  • Imaging
  • Opioid receptor
  • Radiometal

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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