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 - Funding Information:
We thank Drs. Wei Wycoff, Patrick Cavins and Susan Lever for assistance with acquisition and interpretation of 13 C NMR data. We thank the National Institutes of Health , National Cancer Institute ( P50CA103130 : Center for Single Photon-Emitting Cancer Imaging Agents) for support of this research. We also acknowledge resources and facilities provided by the Harry S. Truman Memorial Veterans' Hospital, the University of Missouri Life Sciences Mission Enhancement Program, and NSF (CHE-95-31247; DBI-0070359) and NIH (S10RR11962; S10RR022341) awards for NMR instrumentation. This work does not represent the views of the United States Department of Veterans Affairs.
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 -