Structure–Activity Relationship Studies of Pyridine-Based Ligands and Identification of a Fluorinated Derivative for Positron Emission Tomography Imaging of Cannabinoid Type 2 Receptors

The cannabinoid type 2 (CB2) receptor has emerged as a valuable
target for therapy and imaging of immune-mediated pathologies. With
the aim to find a suitable radiofluorinated analogue of the previously
reported CB2 positron emission tomography (PET) radioligand [11C]­RSR-056, 38 fluorinated derivatives were synthesized and
tested by in vitro binding assays. With a Ki (hCB2) of 6 nM and a selectivity factor of nearly 700 over cannabinoid
type 1 receptors, target compound 3 exhibited optimal
in vitro properties and was selected for evaluation as a PET radioligand.
[18F]3 was obtained in an average radiochemical
yield of 11 ± 4% and molar activities between 33 and 114 GBq/μmol.
Specific binding of [18F]3 to CB2 was demonstrated
by in vitro autoradiography and in vivo PET experiments using the
CB2 ligand GW-405 833. Metabolite analysis revealed only intact
[18F]3 in the rat brain. [18F]3 detected CB2 upregulation in human amyotrophic lateral sclerosis
spinal cord tissue and may thus become a candidate for diagnostic
use in humans.