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2-(4-Methylsulfonylphenyl)pyrimidines as Prospective Radioligands for Imaging Cyclooxygenase-2 with PET—Synthesis, Triage, and Radiolabeling
Cyclooxygenase 2 (COX-2) is an inducible enzyme responsible for the conversion of arachidonic acid into the prostaglandins, PGG2 and PGH2. Expression of this enzyme increases in inflammation. Therefore, the development of probes for imaging COX-2 with positron emission tomography (PET) has gained in...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278313/ https://www.ncbi.nlm.nih.gov/pubmed/30400142 http://dx.doi.org/10.3390/molecules23112850 |
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author | Cortes-Salva, Michelle Y. Shrestha, Stal Singh, Prachi Morse, Cheryl L. Jenko, Kimberly J. Montero Santamaria, Jose A. Zoghbi, Sami S. Innis, Robert B. Pike, Victor W. |
author_facet | Cortes-Salva, Michelle Y. Shrestha, Stal Singh, Prachi Morse, Cheryl L. Jenko, Kimberly J. Montero Santamaria, Jose A. Zoghbi, Sami S. Innis, Robert B. Pike, Victor W. |
author_sort | Cortes-Salva, Michelle Y. |
collection | PubMed |
description | Cyclooxygenase 2 (COX-2) is an inducible enzyme responsible for the conversion of arachidonic acid into the prostaglandins, PGG2 and PGH2. Expression of this enzyme increases in inflammation. Therefore, the development of probes for imaging COX-2 with positron emission tomography (PET) has gained interest because they could be useful for the study of inflammation in vivo, and for aiding anti-inflammatory drug development targeting COX-2. Nonetheless, effective PET radioligands are still lacking. We synthesized eleven COX-2 inhibitors based on a 2(4-methylsulfonylphenyl)pyrimidine core from which we selected three as prospective PET radioligands based on desirable factors, such as high inhibitory potency for COX-2, very low inhibitory potency for COX-1, moderate lipophilicity, and amenability to labeling with a positron-emitter. These inhibitors, namely 6-methoxy-2-(4-(methylsulfonyl)phenyl-N-(thiophen-2ylmethyl)pyrimidin-4-amine (17), the 6-fluoromethyl analogue (20), and the 6-(2-fluoroethoxy) analogue (27), were labeled in useful yields and with high molar activities by treating the 6-hydroxy analogue (26) with [(11)C]iodomethane, [(18)F]2-fluorobromoethane, and [d(2)-(18)F]fluorobromomethane, respectively. [(11)C]17, [(18)F]20, and [d(2)-(18)F]27 were readily purified with HPLC and formulated for intravenous injection. These methods allow these radioligands to be produced for comparative evaluation as PET radioligands for measuring COX-2 in healthy rhesus monkey and for assessing their abilities to detect inflammation. |
format | Online Article Text |
id | pubmed-6278313 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-62783132018-12-13 2-(4-Methylsulfonylphenyl)pyrimidines as Prospective Radioligands for Imaging Cyclooxygenase-2 with PET—Synthesis, Triage, and Radiolabeling Cortes-Salva, Michelle Y. Shrestha, Stal Singh, Prachi Morse, Cheryl L. Jenko, Kimberly J. Montero Santamaria, Jose A. Zoghbi, Sami S. Innis, Robert B. Pike, Victor W. Molecules Article Cyclooxygenase 2 (COX-2) is an inducible enzyme responsible for the conversion of arachidonic acid into the prostaglandins, PGG2 and PGH2. Expression of this enzyme increases in inflammation. Therefore, the development of probes for imaging COX-2 with positron emission tomography (PET) has gained interest because they could be useful for the study of inflammation in vivo, and for aiding anti-inflammatory drug development targeting COX-2. Nonetheless, effective PET radioligands are still lacking. We synthesized eleven COX-2 inhibitors based on a 2(4-methylsulfonylphenyl)pyrimidine core from which we selected three as prospective PET radioligands based on desirable factors, such as high inhibitory potency for COX-2, very low inhibitory potency for COX-1, moderate lipophilicity, and amenability to labeling with a positron-emitter. These inhibitors, namely 6-methoxy-2-(4-(methylsulfonyl)phenyl-N-(thiophen-2ylmethyl)pyrimidin-4-amine (17), the 6-fluoromethyl analogue (20), and the 6-(2-fluoroethoxy) analogue (27), were labeled in useful yields and with high molar activities by treating the 6-hydroxy analogue (26) with [(11)C]iodomethane, [(18)F]2-fluorobromoethane, and [d(2)-(18)F]fluorobromomethane, respectively. [(11)C]17, [(18)F]20, and [d(2)-(18)F]27 were readily purified with HPLC and formulated for intravenous injection. These methods allow these radioligands to be produced for comparative evaluation as PET radioligands for measuring COX-2 in healthy rhesus monkey and for assessing their abilities to detect inflammation. MDPI 2018-11-02 /pmc/articles/PMC6278313/ /pubmed/30400142 http://dx.doi.org/10.3390/molecules23112850 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Cortes-Salva, Michelle Y. Shrestha, Stal Singh, Prachi Morse, Cheryl L. Jenko, Kimberly J. Montero Santamaria, Jose A. Zoghbi, Sami S. Innis, Robert B. Pike, Victor W. 2-(4-Methylsulfonylphenyl)pyrimidines as Prospective Radioligands for Imaging Cyclooxygenase-2 with PET—Synthesis, Triage, and Radiolabeling |
title | 2-(4-Methylsulfonylphenyl)pyrimidines as Prospective Radioligands for Imaging Cyclooxygenase-2 with PET—Synthesis, Triage, and Radiolabeling |
title_full | 2-(4-Methylsulfonylphenyl)pyrimidines as Prospective Radioligands for Imaging Cyclooxygenase-2 with PET—Synthesis, Triage, and Radiolabeling |
title_fullStr | 2-(4-Methylsulfonylphenyl)pyrimidines as Prospective Radioligands for Imaging Cyclooxygenase-2 with PET—Synthesis, Triage, and Radiolabeling |
title_full_unstemmed | 2-(4-Methylsulfonylphenyl)pyrimidines as Prospective Radioligands for Imaging Cyclooxygenase-2 with PET—Synthesis, Triage, and Radiolabeling |
title_short | 2-(4-Methylsulfonylphenyl)pyrimidines as Prospective Radioligands for Imaging Cyclooxygenase-2 with PET—Synthesis, Triage, and Radiolabeling |
title_sort | 2-(4-methylsulfonylphenyl)pyrimidines as prospective radioligands for imaging cyclooxygenase-2 with pet—synthesis, triage, and radiolabeling |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278313/ https://www.ncbi.nlm.nih.gov/pubmed/30400142 http://dx.doi.org/10.3390/molecules23112850 |
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