title: 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.
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,δand 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 D7.4values were -2.21 to -1.66. In comparison, DPN is lipophilic, with a log D7.4of +2.25. Further study in vivo is warranted to assess the suitability of these [111In]-labeled DPN-DOTA conjugates for imaging trials.
authors.affiliation: Department of Radiology, University of Missouri, Columbia, MO 65211, USA; Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201, USA.
authors.forename: Shefali
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: Department of Radiology, University of Missouri, Columbia, MO 65211, USA; Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201, USA.
authors.forename: Emily A
authors.initials: EA
authors.lastname: Fergason-Cantrell
authors.affiliation: Department of Chemistry, University of Missouri, Columbia, MO 65212, USA; Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201, USA.
authors.forename: Roger I
authors.initials: RI
authors.lastname: Nahas
authors.affiliation: Department of Radiology, University of Missouri, Columbia, MO 65211, USA; Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Lever
keywords: Bioconjugate; Diprenorphine; Imaging; Opioid receptor; Radiometal