Pharmacological Characterization of Low-to-Moderate Affinity Opioid Receptor Agonists and Brain Imaging with (18)F-Labeled Derivatives in Rats

[Image: see text] The 3,4-dichloro-N-(1-(dimethylamino)cyclohexyl)methyl benzamide scaffold was studied as a template for (18)F-positron emission tomography ((18)F-PET) radiotracer development emphasizing sensitivity to changes in opioid receptor (OR) occupancy over high affinity. Agonist potency, binding affinity, and relevant pharmacological parameters of 15 candidates were investigated. Two promising compounds 3b and 3e with μ-OR (MOR) selective agonist activity in the moderate range (EC(50) = 1–100 nM) were subjected to (18)F-fluorination, autoradiography, and small-animal PET imaging. Radioligands [(18)F]3b and [(18)F]3e were obtained in activity yields of 21 ± 5 and 23 ± 4% and molar activities of 25–40 and 200–300 GBq/μmol, respectively. Displaceable binding matching MOR distribution in the brain was confirmed by imaging. Radioligands showed a rapid pharmacokinetic profile; however, metabolite-corrected, blood-based modeling was required for data analysis. Observed BP(ND) was low, although treatment with naloxone leads to a marked decrease in specific binding, confirming the discovery of a new template for (18)F-labeled OR-agonist PET ligands.