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, 146, 409-422

Optimization of the Metabolic Stability of a Fluorinated Cannabinoid Receptor Subtype 2 (CB 2) Ligand Designed for PET Studies

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Optimization of the Metabolic Stability of a Fluorinated Cannabinoid Receptor Subtype 2 (CB 2) Ligand Designed for PET Studies

Dominik Heimann et al. Eur J Med Chem.

Abstract

The central CB2 receptor represents a promising target for the treatment of neuroinflammatory diseases as CB2 activation mediates anti-inflammatory effects. Recently, the F-18 labeled PET radiotracer [18F]7a was reported, which shows high CB2 affinity and high selectivity over the CB1 subtype but low metabolic stability due to hydrolysis of the amide group. Based on these findings twelve bioisosteres of 7a were synthesized containing a non-hydrolysable functional group instead of the amide group. The secondary amine 23a (Ki = 7.9 nM) and the ketone 26a (Ki = 8.6 nM) displayed high CB2 affinity and CB2:CB1 selectivity in in vitro radioligand binding studies. Incubation of 7a, 23a and 26a with mouse liver microsomes and LC-quadrupole-MS analysis revealed a slightly higher metabolic stability of secondary amine 23a, but a remarkably higher stability of ketone 26a in comparison to amide 7a. Furthermore, a logD7.4 value of 5.56 ± 0.08 was determined for ketone 26a by micro shake-flask method and LC-MS quantification.

Keywords: Amide bioisosteres; CB(2) receptor ligands; Fluorinated carbazole derivatives; Identification of metabolites; Metabolic stabilization; PET; Structure affinity relationships.

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