TY - JOUR
T1 - Synthesis and opioid receptor binding of indium (III) and [111In]-labeled macrocyclic conjugates of diprenorphine
T2 - novel ligands designed for imaging studies of peripheral opioid receptors
AU - Srivastava, Shefali
AU - Fergason-Cantrell, Emily A.
AU - Nahas, Roger I.
AU - Lever, John R.
N1 - Publisher Copyright:
© 2016 Elsevier Ltd
PY - 2016
Y1 - 2016
N2 - 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 D7.4values 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.
AB - 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 D7.4values 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.
KW - Bioconjugate
KW - Diprenorphine
KW - Imaging
KW - Opioid receptor
KW - Radiometal
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U2 - 10.1016/j.tet.2016.08.015
DO - 10.1016/j.tet.2016.08.015
M3 - Article
AN - SCOPUS:84986278339
SN - 0040-4020
VL - 72
SP - 6127
EP - 6135
JO - Tetrahedron
JF - Tetrahedron
IS - 40
ER -