Structure–Activity Relationship Studies of Pyridine-Based Ligands and Identification of a Fluorinated Derivative for Positron Emission Tomography Imaging of Cannabinoid Type 2 Receptors

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 [11C]­RSR-056, 38 fluorinated derivat...

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Published inJournal of medicinal chemistry Vol. 62; no. 24; pp. 11165 - 11181
Main Authors Haider, Achi, 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, Herde, Adrienne Müller, Keller, Claudia, Schibli, Roger, Mu, Linjing, Grether, Uwe, Ametamey, Simon M.
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 26.12.2019
Amer Chemical Soc
Subjects
Animals
Brain - diagnostic imaging
Brain - metabolism
Chemistry, Medicinal
Cyclic AMP - metabolism
Fluorine Radioisotopes - chemistry
Fluorine Radioisotopes - metabolism
Hepatocytes - metabolism
Humans
Life Sciences & Biomedicine
Ligands
Male
Mice
Mice, Inbred C57BL
Molecular Structure
Neuroimaging - methods
Pharmacology & Pharmacy
Positron-Emission Tomography - methods
Protein Conformation
Pyridines - chemistry
Radiochemistry
Radiopharmaceuticals - chemistry
Radiopharmaceuticals - metabolism
Rats
Rats, Wistar
Receptor, Cannabinoid, CB2 - chemistry
Receptor, Cannabinoid, CB2 - metabolism
Science & Technology
Structure-Activity Relationship
TARGET
CB2 RECEPTORS
RADIOLIGAND
VIVO EVALUATION
HIGH-AFFINITY
BINDING
AGONIST
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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 [11C]­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. [18F]3 was obtained in an average radiochemical yield of 11 ± 4% and molar activities between 33 and 114 GBq/μmol. Specific binding of [18F]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 [18F]3 in the rat brain. [18F]3 detected CB2 upregulation in human amyotrophic lateral sclerosis spinal cord tissue and may thus become a candidate for diagnostic use in humans.
AbstractList 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 [11C]RSR-056, 38 fluorinated derivatives were synthesized and tested by in vitro binding assays. With a Ki (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. [18F]3 was obtained in an average radiochemical yield of 11 ± 4% and molar activities between 33 and 114 GBq/μmol. Specific binding of [18F]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 [18F]3 in the rat brain. [18F]3 detected CB2 upregulation in human amyotrophic lateral sclerosis spinal cord tissue and may thus become a candidate for diagnostic use in humans.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 [11C]RSR-056, 38 fluorinated derivatives were synthesized and tested by in vitro binding assays. With a Ki (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. [18F]3 was obtained in an average radiochemical yield of 11 ± 4% and molar activities between 33 and 114 GBq/μmol. Specific binding of [18F]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 [18F]3 in the rat brain. [18F]3 detected CB2 upregulation in human amyotrophic lateral sclerosis spinal cord tissue and may thus become a candidate for diagnostic use in humans.
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 [11C]­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. [18F]3 was obtained in an average radiochemical yield of 11 ± 4% and molar activities between 33 and 114 GBq/μmol. Specific binding of [18F]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 [18F]3 in the rat brain. [18F]3 detected CB2 upregulation in human amyotrophic lateral sclerosis spinal cord tissue and may thus become a candidate for diagnostic use in humans.
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 [ C]RSR-056, 38 fluorinated derivatives were synthesized and tested by in vitro binding assays. With a (hCB2) of 6 nM and a selectivity factor of nearly 700 over cannabinoid type 1 receptors, target compound exhibited optimal in vitro properties and was selected for evaluation as a PET radioligand. [ F] was obtained in an average radiochemical yield of 11 ± 4% and molar activities between 33 and 114 GBq/μmol. Specific binding of [ F] 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 [ F] in the rat brain. [ F] detected CB2 upregulation in human amyotrophic lateral sclerosis spinal cord tissue and may thus become a candidate for diagnostic use in humans.
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 [C-11]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. [F-18]3 was obtained in an average radiochemical yield of 11 +/- 4% and molar activities between 33 and 114 GBq/mu mol. Specific binding of [F-18]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 [F-18]3 in the rat brain. [18F]3 detected CB2 upregulation in human amyotrophic lateral sclerosis spinal cord tissue and may thus become a candidate for diagnostic use in humans.
Author Herde, Adrienne Müller
Mu, Linjing
Bürkler, Markus
Guba, Wolfgang
Weber, Markus
Gobbi, Luca
Ullmer, Christoph
Knuesel, Irene
Kretz, Julian
Honer, Michael
Bartelmus, Christian
Fingerle, Jürgen
Haider, Achi
Brink, Andreas
Atz, Kenneth
Keller, Claudia
Grether, Uwe
Schibli, Roger
Ametamey, Simon M.
Ahmed, Hazem
AuthorAffiliation Neuromuscular Diseases Unit/ALS Clinic
Department of Nuclear Medicine
Institute of Pharmaceutical Sciences
Pharma Research and Early Development
University Hospital Zurich
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Keywords TARGET
CB2 RECEPTORS
RADIOLIGAND
VIVO EVALUATION
HIGH-AFFINITY
BINDING
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Snippet 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...
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...
Source Web of Science
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acs
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StartPage 11165
SubjectTerms Animals
Brain - diagnostic imaging
Brain - metabolism
Chemistry, Medicinal
Cyclic AMP - metabolism
Fluorine Radioisotopes - chemistry
Fluorine Radioisotopes - metabolism
Hepatocytes - metabolism
Humans
Life Sciences & Biomedicine
Ligands
Male
Mice
Mice, Inbred C57BL
Molecular Structure
Neuroimaging - methods
Pharmacology & Pharmacy
Positron-Emission Tomography - methods
Protein Conformation
Pyridines - chemistry
Radiochemistry
Radiopharmaceuticals - chemistry
Radiopharmaceuticals - metabolism
Rats
Rats, Wistar
Receptor, Cannabinoid, CB2 - chemistry
Receptor, Cannabinoid, CB2 - metabolism
Science & Technology
Structure-Activity Relationship
Title Structure–Activity Relationship Studies of Pyridine-Based Ligands and Identification of a Fluorinated Derivative for Positron Emission Tomography Imaging of Cannabinoid Type 2 Receptors
URI http://dx.doi.org/10.1021/acs.jmedchem.9b01280
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https://www.proquest.com/docview/2317583886
Volume 62
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