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Synthesis, NMR characterization and pharmacological evaluation of ligands derived from diprenorphine for central opioid receptors imaging
Author(s) -
Bourrel François,
Massou Stéphane,
Baltas Michel,
Bergon Michel,
Tafani Mathieu,
Esquere JeanPaul,
Tisnès Pierre,
Prigent Yann
Publication year - 2001
Publication title -
journal of physical organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.325
H-Index - 66
eISSN - 1099-1395
pISSN - 0894-3230
DOI - 10.1002/poc.423
Subject(s) - diprenorphine , chemistry , stereochemistry , alcohol , nuclear magnetic resonance spectroscopy , receptor , ligand (biochemistry) , opioid receptor , opioid , organic chemistry , biochemistry
The aim of this work was to explore the synthesis of a tosylated derivative of diprenorphine (DPN) able to be radiolabeled with either fluorine‐18 or iodine‐123, making it suitable for PET or SPECT imaging studies of central opioid receptors, respectively. The strategy was based on the reactivity of the C‐19 alcohol tertiary function. As an unexpected deacetylation of the phenolic function of the diprenorphine occurred, the prosthetic group reacted with the deprotected C‐3 phenolic function instead of the C‐19 alcohol group. UV spectroscopy and 1 H and 13 C NMR studies provided good evidence for the 3‐phenolic substituted diprenorphine structure. Thorough 2D NMR experiments such as 1 H– 1 H COSY, 1 H– 1 H TOCSY, 1 H– 13 C HMQC, 1 H– 13 C HMBC and 1 H– 1 H NOESY allowed us to assign fully 3‐ O ‐[( Z )‐4‐fluorobut‐2‐enyl] diprenorphine ( 10a ) and gave us an unambiguous proof of the C‐3 prosthetic group position. In vitro binding studies showed low affinity for both fluoro and iodo derivatives of diprenorphine, K i = 0.31 ± 0.05 and 0.09 ± 0.03 µ M , respectively, for mouse brain membranes, these inhibition constants also being in agreement with a 3‐phenolic substituted structure. Copyright © 2001 John Wiley & Sons, Ltd.