当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Pharmacological Characterization of Low-to-Moderate Affinity Opioid Receptor Agonists and Brain Imaging with 18F-Labeled Derivatives in Rats.

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

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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Ott J,Spilhaug MM,Maschauer S,Rafique W,Jakobsson JE,Hartvig K,Hübner H,Gmeiner P,Prante O,Riss PJ

doi

10.1021/acs.jmedchem.0c00683

subject

Has Abstract

pub_date

2020-09-10 00:00:00

pages

9484-9499

issue

17

eissn

0022-2623

issn

1520-4804

journal_volume

63

pub_type

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