Synthesis, NMR characterization and pharmacological evaluation of ligands derived from diprenorphine for central opioid receptors imaging

Abstract

AbstractThe 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 1H and 13C NMR studies provided good evidence for the 3‐phenolic substituted diprenorphine structure. Thorough 2D NMR experiments such as 1H–1H COSY, 1H–1H TOCSY, 1H–13C HMQC, 1H–13C HMBC and 1H–1H 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, Ki = 0.31 ± 0.05 and 0.09 ± 0.03 µM, respectively, for mouse brain membranes, these inhibition constants also being in agreement with a 3‐phenolic substituted structure. Copyright © 2001 John Wiley & Sons, Ltd.