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

Julian Ott,Waqas Rafique,Simone Maschauer,Olaf Prante,Karoline Hartvig,Patrick J Riss,Harald Hübner,Jimmy E Jakobsson,Peter Gmeiner,Mona M Spilhaug

doi:10.1021/acs.jmedchem.0c00683

Abstract

The 3,4-dichloro-N-(1-(dimethylamino)cyclohexyl)methyl benzamide scaffold was studied as a template for 18F-positron emission tomography (18F-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 (EC50 = 1–100 nM) were subjected to 18F-fluorination, autoradiography, and small-animal PET imaging. Radioligands [18F]3b and [18F]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 BPND was low, although treatment with naloxone leads to a marked decrease in specific binding, confirming the discovery of a new template for 18F-labeled OR-agonist PET ligands.

Highlights

Opioid receptors (ORs) are G-protein-coupled receptors (GPCR) of some prominence in quantitative imaging studies
We demonstrated that the radioligand [11C]3a showed a promising performance in rodent positron emission tomography (PET) studies.[15]
The parent structure 3a does not contain any native fluorine atoms, we chose it as a design template for novel OR ligands within a molecular weight range of 280−380 g/mol

Summary

Introduction

Opioid receptors (ORs) are G-protein-coupled receptors (GPCR) of some prominence in quantitative imaging studies. Because opioid signaling is implicated in a variety of central precipitations of behavior and disease, the study of ORs, μ (MOR), δ (DOR), and κ (KOR), is of interest in the scientific context of decision making, addiction, and pain processing.[1,2] These subtypes share a common amino acid sequence but vary widely in both their endogeneous and exogeneous ligands and their individual physiological functions. The highest fractions of expression of any subtype are found in the substantia nigra (66% KOR) and the thalamus (67% MOR), reflecting the need for a subtype-selective radioligand with sufficient binding selectivity in vivo when attempting to study the function and role of a single OR in the brain.[1−7] In recent years, a new interest in OR radioligands developed, for example, because of an opioid abuse crisis. The limited availability, toxicity, and short half-life of [11C]carfentanil, which is the only MOR-selective positron emission tomography (PET) ligand in use, prompted us to explore an alternative path.[5−8] Our approach was motivated by ongoing discussions on the mechanism of displacement of the PET ligand from the OR receptor by endogeneous ligands and drug molecules.[7−9]

Objectives

Methods

Results

Conclusion