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. 2016 Oct 6;72(40):6127-6135.
doi: 10.1016/j.tet.2016.08.015. Epub 2016 Aug 4.

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  1 , Emily A Fergason-Cantrell  1 , Roger I Nahas  2 , John R Lever  1
Affiliations

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 et al. Tetrahedron. .

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.

Keywords: Bioconjugate; Diprenorphine; Imaging; Opioid receptor; Radiometal.

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Figures

Fig. 1
Fig. 1
Structures of diprenorphine (DPN), representative radiolabeled analogs, and a cartoon of a hypothetical radiometal-labeled DPN conjugate binding to μ, δ and κ opioid receptors.
Fig. 2
Fig. 2
Top panel: Reversed-phase HPLC chromatograms of purified [111In]11. Bottom panel: Purified [111In]11 coinjected with a standard mixture prepared from 11 and precursor 9 to demonstrate coelution, as well as resolution of metal complex from precursor (see Experimental 4.3 for conditions).
Scheme 1
Scheme 1
Synthesis of triol 1 from DPN, and conversion to tosyl-protected 2.
Scheme 2
Scheme 2
Synthesis of C6–O-alkylamino-DPN derivatives 5 and 8.
Scheme 3
Scheme 3
Synthesis of DPN-DOTA conjugates 9 and 10, and their conversion to indium (III) and [111In]-labeled complexes 11 and 12.
See this image and copyright information in PMC

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