Discovery of a High Affinity and Selective Pyridine Analog as a Potential Positron Emission Tomography Imaging Agent for Cannabinoid Type 2 Receptor

As
part of our efforts to develop CB2 PET imaging agents, we investigated
2,5,6-substituted pyridines as a novel class of potential CB2 PET
ligands. A total of 21 novel compounds were designed, synthesized,
and evaluated for their potency and binding properties toward human
and rodent CB1 and CB2. The most promising ligand 6a was
radiolabeled with carbon-11 to yield 16 ([11C]­RSR-056). Specific binding of 16 to CB2-positive spleen
tissue of rats and mice was demonstrated by in vitro autogadiography and verified in vivo in PET and biodistribution experiments.
Furthermore, 16 was evaluated in a lipopolysaccharid
(LPS) induced murine model of neuroinflammation. Brain radioactivity
was strikingly higher in the LPS-treated mice than the control mice.
Compound 16 is a promising radiotracer for imaging CB2
in rodents. It might serve as a tool for the investigation of CB2
receptor expression levels in healthy tissues and different neuroinflammatory
disorders in humans.