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Radiofluorination and biological evaluation of N-aryl-oxadiazolyl-propionamides as potential radioligands for PET imaging of cannabinoid CB(2) receptors

BACKGROUND: The level of expression of cannabinoid receptor type 2 (CB(2)R) in healthy and diseased brain has not been fully elucidated. Therefore, there is a growing interest to assess the regional expression of CB(2)R in the brain. Positron emission tomography (PET) is an imaging technique, which...

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Autores principales: Teodoro, Rodrigo, Moldovan, Rareş-Petru, Lueg, Corinna, Günther, Robert, Donat, Cornelius K, Ludwig, Friedrich-Alexander, Fischer, Steffen, Deuther-Conrad, Winnie, Wünsch, Bernhard, Brust, Peter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3856494/
https://www.ncbi.nlm.nih.gov/pubmed/24063584
http://dx.doi.org/10.1186/2191-2858-3-11
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author Teodoro, Rodrigo
Moldovan, Rareş-Petru
Lueg, Corinna
Günther, Robert
Donat, Cornelius K
Ludwig, Friedrich-Alexander
Fischer, Steffen
Deuther-Conrad, Winnie
Wünsch, Bernhard
Brust, Peter
author_facet Teodoro, Rodrigo
Moldovan, Rareş-Petru
Lueg, Corinna
Günther, Robert
Donat, Cornelius K
Ludwig, Friedrich-Alexander
Fischer, Steffen
Deuther-Conrad, Winnie
Wünsch, Bernhard
Brust, Peter
author_sort Teodoro, Rodrigo
collection PubMed
description BACKGROUND: The level of expression of cannabinoid receptor type 2 (CB(2)R) in healthy and diseased brain has not been fully elucidated. Therefore, there is a growing interest to assess the regional expression of CB(2)R in the brain. Positron emission tomography (PET) is an imaging technique, which allows quantitative monitoring of very low amounts of radiolabelled compounds in living organisms at high temporal and spatial resolution and, thus, has been widely used as a diagnostic tool in nuclear medicine. Here, we report on the radiofluorination of N-aryl-oxadiazolyl-propionamides at two different positions in the lead structure and on the biological evaluation of the potential of the two tracers [(18)F]1 and [(18)F]2 as CB(2) receptor PET imaging agents. RESULTS: High binding affinity and specificity towards CB(2) receptors of the lead structure remained unaffected by the structural changes such as the insertion of the aliphatic and aromatic fluorine in the selected labelling sites of 1 and 2. Aliphatic and aromatic radiofluorinations were optimized, and [(18)F]1 and [(18)F]2 were achieved in radiochemical yields of ≥30% with radiochemical purities of ≥98% and specific activities of 250 to 450 GBq/μmol. Organ distribution studies in female CD1 mice revealed that both radiotracers cross the blood–brain barrier (BBB) but undergo strong peripheral metabolism. At 30 min after injection, unmetabolized [(18)F]1 and [(18)F]2 accounted for 60% and 2% as well as 68% and 88% of the total activity in the plasma and brain, respectively. The main radiometabolite of [(18)F]2 could be identified as the free acid [(18)F]10, which has no affinity towards the CB(1) and CB(2) receptors but can cross the BBB. CONCLUSIONS: N-aryl-oxadiazolyl-propionamides can successfully be radiolabelled with (18)F at different positions. Fluorine substitution at these positions did not affect affinity and specificity towards CB(2)R. Despite a promising in vitro behavior, a rather rapid peripheral metabolism of [(18)F]1 and [(18)F]2 in mice and the generation of brain permeable radiometabolites hamper the application of these radiotracers in vivo. However, it is expected that future synthetic modification aiming at a replacement of metabolically susceptible structural elements of [(18)F]1 and [(18)F]2 will help to elucidate the potential of this class of compounds for CB(2)R PET studies.
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spelling pubmed-38564942013-12-11 Radiofluorination and biological evaluation of N-aryl-oxadiazolyl-propionamides as potential radioligands for PET imaging of cannabinoid CB(2) receptors Teodoro, Rodrigo Moldovan, Rareş-Petru Lueg, Corinna Günther, Robert Donat, Cornelius K Ludwig, Friedrich-Alexander Fischer, Steffen Deuther-Conrad, Winnie Wünsch, Bernhard Brust, Peter Org Med Chem Lett Original Article BACKGROUND: The level of expression of cannabinoid receptor type 2 (CB(2)R) in healthy and diseased brain has not been fully elucidated. Therefore, there is a growing interest to assess the regional expression of CB(2)R in the brain. Positron emission tomography (PET) is an imaging technique, which allows quantitative monitoring of very low amounts of radiolabelled compounds in living organisms at high temporal and spatial resolution and, thus, has been widely used as a diagnostic tool in nuclear medicine. Here, we report on the radiofluorination of N-aryl-oxadiazolyl-propionamides at two different positions in the lead structure and on the biological evaluation of the potential of the two tracers [(18)F]1 and [(18)F]2 as CB(2) receptor PET imaging agents. RESULTS: High binding affinity and specificity towards CB(2) receptors of the lead structure remained unaffected by the structural changes such as the insertion of the aliphatic and aromatic fluorine in the selected labelling sites of 1 and 2. Aliphatic and aromatic radiofluorinations were optimized, and [(18)F]1 and [(18)F]2 were achieved in radiochemical yields of ≥30% with radiochemical purities of ≥98% and specific activities of 250 to 450 GBq/μmol. Organ distribution studies in female CD1 mice revealed that both radiotracers cross the blood–brain barrier (BBB) but undergo strong peripheral metabolism. At 30 min after injection, unmetabolized [(18)F]1 and [(18)F]2 accounted for 60% and 2% as well as 68% and 88% of the total activity in the plasma and brain, respectively. The main radiometabolite of [(18)F]2 could be identified as the free acid [(18)F]10, which has no affinity towards the CB(1) and CB(2) receptors but can cross the BBB. CONCLUSIONS: N-aryl-oxadiazolyl-propionamides can successfully be radiolabelled with (18)F at different positions. Fluorine substitution at these positions did not affect affinity and specificity towards CB(2)R. Despite a promising in vitro behavior, a rather rapid peripheral metabolism of [(18)F]1 and [(18)F]2 in mice and the generation of brain permeable radiometabolites hamper the application of these radiotracers in vivo. However, it is expected that future synthetic modification aiming at a replacement of metabolically susceptible structural elements of [(18)F]1 and [(18)F]2 will help to elucidate the potential of this class of compounds for CB(2)R PET studies. Springer 2013-09-24 /pmc/articles/PMC3856494/ /pubmed/24063584 http://dx.doi.org/10.1186/2191-2858-3-11 Text en Copyright © 2013 Teodoro et al.; licensee Springer. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Article
Teodoro, Rodrigo
Moldovan, Rareş-Petru
Lueg, Corinna
Günther, Robert
Donat, Cornelius K
Ludwig, Friedrich-Alexander
Fischer, Steffen
Deuther-Conrad, Winnie
Wünsch, Bernhard
Brust, Peter
Radiofluorination and biological evaluation of N-aryl-oxadiazolyl-propionamides as potential radioligands for PET imaging of cannabinoid CB(2) receptors
title Radiofluorination and biological evaluation of N-aryl-oxadiazolyl-propionamides as potential radioligands for PET imaging of cannabinoid CB(2) receptors
title_full Radiofluorination and biological evaluation of N-aryl-oxadiazolyl-propionamides as potential radioligands for PET imaging of cannabinoid CB(2) receptors
title_fullStr Radiofluorination and biological evaluation of N-aryl-oxadiazolyl-propionamides as potential radioligands for PET imaging of cannabinoid CB(2) receptors
title_full_unstemmed Radiofluorination and biological evaluation of N-aryl-oxadiazolyl-propionamides as potential radioligands for PET imaging of cannabinoid CB(2) receptors
title_short Radiofluorination and biological evaluation of N-aryl-oxadiazolyl-propionamides as potential radioligands for PET imaging of cannabinoid CB(2) receptors
title_sort radiofluorination and biological evaluation of n-aryl-oxadiazolyl-propionamides as potential radioligands for pet imaging of cannabinoid cb(2) receptors
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3856494/
https://www.ncbi.nlm.nih.gov/pubmed/24063584
http://dx.doi.org/10.1186/2191-2858-3-11
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