Development of fluorinated CB2 receptor agonists for PET studies

Abstract A convergent strategy was followed to modify systematically carbazole based CB 2 receptor ligands. The length of the N -(fluoroalkyl) group ( n in 7 ), the length of the alkanamide ( m in 7 ) and the substitution pattern of the phenyl moiety (X and Y in 7 ) were varied systematically. The highest CB 2 affinity was found for the 2-fluoroethyl substituted carbazole derivative 20a ( K i  = 5.8 nM) containing the propionamide and the 2-bromo-4-fluorophenyl moiety. According to docking studies 20a fits nicely into the binding pocket of the CB 2 receptor, but elongation of the fluoroethyl side chain leads to a different binding mode of the ligands. The high CB 2 affinity together with the high selectivity over the CB 2 subtype qualifies the fluoroethyl derivative 20a to be developed as a PET tracer.