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Structure-activity relationship studies of pyridine-based ligands and identification of a fluorinated derivative for positron emission tomography imaging of cannabinoid type 2 receptors


Haider, Ahmed; Kretz, Julian; Gobbi, Luca; Ahmed, Hazem; Atz, Kenneth; Bürkler, Markus; Bartelmus, Christian; Fingerle, Jürgen; Guba, Wolfgang; Ullmer, Christoph; Honer, Michael; Knuesel, Irene; Weber, Markus; Brink, Andreas; Müller Herde, Adrienne; Keller, Claudia; Schibli, Roger; Mu, Linjing; Grether, Uwe; Ametamey, Simon M (2019). Structure-activity relationship studies of pyridine-based ligands and identification of a fluorinated derivative for positron emission tomography imaging of cannabinoid type 2 receptors. Journal of Medicinal Chemistry, 62(24):11165-11181.

Abstract

The cannabinoid type 2 (CB2) receptor has emerged as a valuable target for therapy and imaging of immune-mediated pathologies. With the aim to find a suitable radiofluorinated analogue of the previously reported CB2 positron emission tomography (PET) radioligand [$^{11}$C]RSR-056, 38 fluorinated derivatives were synthesized and tested by in vitro binding assays. With a K$_{i}$ (hCB2) of 6 nM and a selectivity factor of nearly 700 over cannabinoid type 1 receptors, target compound 3 exhibited optimal in vitro properties and was selected for evaluation as a PET radioligand. [$^{18}$F]3 was obtained in an average radiochemical yield of 11 ± 4% and molar activities between 33 and 114 GBq/μmol. Specific binding of [$^{18}$F]3 to CB2 was demonstrated by in vitro autoradiography and in vivo PET experiments using the CB2 ligand GW-405 833. Metabolite analysis revealed only intact [$^{18}$F]3 in the rat brain. [$^{18}$F]3 detected CB2 upregulation in human amyotrophic lateral sclerosis spinal cord tissue and may thus become a candidate for diagnostic use in humans.

Abstract

The cannabinoid type 2 (CB2) receptor has emerged as a valuable target for therapy and imaging of immune-mediated pathologies. With the aim to find a suitable radiofluorinated analogue of the previously reported CB2 positron emission tomography (PET) radioligand [$^{11}$C]RSR-056, 38 fluorinated derivatives were synthesized and tested by in vitro binding assays. With a K$_{i}$ (hCB2) of 6 nM and a selectivity factor of nearly 700 over cannabinoid type 1 receptors, target compound 3 exhibited optimal in vitro properties and was selected for evaluation as a PET radioligand. [$^{18}$F]3 was obtained in an average radiochemical yield of 11 ± 4% and molar activities between 33 and 114 GBq/μmol. Specific binding of [$^{18}$F]3 to CB2 was demonstrated by in vitro autoradiography and in vivo PET experiments using the CB2 ligand GW-405 833. Metabolite analysis revealed only intact [$^{18}$F]3 in the rat brain. [$^{18}$F]3 detected CB2 upregulation in human amyotrophic lateral sclerosis spinal cord tissue and may thus become a candidate for diagnostic use in humans.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Nuclear Medicine
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Life Sciences > Molecular Medicine
Life Sciences > Drug Discovery
Language:English
Date:26 December 2019
Deposited On:05 Feb 2020 18:55
Last Modified:29 Jul 2020 13:08
Publisher:American Chemical Society (ACS)
ISSN:0022-2623
OA Status:Closed
Publisher DOI:https://doi.org/10.1021/acs.jmedchem.9b01280
PubMed ID:31751140

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