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

Authors
  • Ott, Julian1
  • Spilhaug, Mona M.2
  • Maschauer, Simone1
  • Rafique, Waqas2
  • Jakobsson, Jimmy E.2
  • Hartvig, Karoline2
  • Hübner, Harald1
  • Gmeiner, Peter1
  • Prante, Olaf1
  • Riss, Patrick J.2, 3
  • 1 Friedrich Alexander University Erlangen-Nürnberg (FAU), Germany , (Germany)
  • 2 Universitetet i Oslo, Norway , (Norway)
  • 3 OUS-UllevÅl, Norway , (Norway)
Type
Published Article
Journal
Journal of Medicinal Chemistry
Publisher
American Chemical Society
Publication Date
Jul 31, 2020
Volume
63
Issue
17
Pages
9484–9499
Identifiers
DOI: 10.1021/acs.jmedchem.0c00683
PMID: 32787100
PMCID: PMC7497404
Source
PubMed Central
License
Unknown

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.

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