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...
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| Published in | Molecules (Basel, Switzerland) Vol. 23; no. 11; p. 2850 |
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| Main Authors | , , , , , , , , |
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| Abstract | 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 [11C]iodomethane, [18F]2-fluorobromoethane, and [d2-18F]fluorobromomethane, respectively. [11C]17, [18F]20, and [d2-18F]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. |
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| AbstractList | 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 [11C]iodomethane, [18F]2-fluorobromoethane, and [d2-18F]fluorobromomethane, respectively. [11C]17, [18F]20, and [d2-18F]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. 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. 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 positronemitter. 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 [11C]iodomethane, [18F]2-fluorobromoethane, and [d2-18F]fluorobromomethane, respectively. [11C]17, [18F]20, and [d2-18F]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.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 positronemitter. 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 [11C]iodomethane, [18F]2-fluorobromoethane, and [d2-18F]fluorobromomethane, respectively. [11C]17, [18F]20, and [d2-18F]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. 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 positronemitter. These inhibitors, namely 6-methoxy-2-(4-(methylsulfonyl)phenyl- -(thiophen-2ylmethyl)pyrimidin-4-amine ( ), the 6-fluoromethyl analogue ( ), and the 6-(2-fluoroethoxy) analogue ( ), were labeled in useful yields and with high molar activities by treating the 6-hydroxy analogue ( ) with [ C]iodomethane, [ F]2-fluorobromoethane, and [ 2- F]fluorobromomethane, respectively. , , and 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. |
| Author | Zoghbi, Sami S. Montero Santamaria, Jose A. Morse, Cheryl L. Jenko, Kimberly J. Innis, Robert B. Cortes-Salva, Michelle Y. Singh, Prachi Shrestha, Stal Pike, Victor W. |
| AuthorAffiliation | Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA; michelle.cortes@nih.gov (M.Y.C.-S.); stal.shrestha@med.miami.edu (S.S.); prachi1singh1@gmail.com (P.S.); morsec@mail.nih.gov (C.L.M.); kimjojenko@gmail.com (K.J.J.); jose.monterosantamaria@nih.gov (J.A.M.S.); zoghbis@mail.nih.gov (S.S.Z.) innisr@mail.nih.gov (R.B.I.) |
| AuthorAffiliation_xml | – name: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA; michelle.cortes@nih.gov (M.Y.C.-S.); stal.shrestha@med.miami.edu (S.S.); prachi1singh1@gmail.com (P.S.); morsec@mail.nih.gov (C.L.M.); kimjojenko@gmail.com (K.J.J.); jose.monterosantamaria@nih.gov (J.A.M.S.); zoghbis@mail.nih.gov (S.S.Z.) innisr@mail.nih.gov (R.B.I.) |
| Author_xml | – sequence: 1 givenname: Michelle Y. orcidid: 0000-0002-2449-2834 surname: Cortes-Salva fullname: Cortes-Salva, Michelle Y. – sequence: 2 givenname: Stal surname: Shrestha fullname: Shrestha, Stal – sequence: 3 givenname: Prachi surname: Singh fullname: Singh, Prachi – sequence: 4 givenname: Cheryl L. surname: Morse fullname: Morse, Cheryl L. – sequence: 5 givenname: Kimberly J. surname: Jenko fullname: Jenko, Kimberly J. – sequence: 6 givenname: Jose A. surname: Montero Santamaria fullname: Montero Santamaria, Jose A. – sequence: 7 givenname: Sami S. surname: Zoghbi fullname: Zoghbi, Sami S. – sequence: 8 givenname: Robert B. surname: Innis fullname: Innis, Robert B. – sequence: 9 givenname: Victor W. orcidid: 0000-0001-9032-2553 surname: Pike fullname: Pike, Victor W. |
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| Keywords | radioligand carbon-11 fluorine-18 COX-2 |
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| SubjectTerms | Alzheimer's disease Carbon carbon-11 COX-2 Drug development Enzymes Fluorine fluorine-18 Inflammation Labeling Ligands Nonsteroidal anti-inflammatory drugs radioligand |
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| Title | 2-(4-Methylsulfonylphenyl)pyrimidines as Prospective Radioligands for Imaging Cyclooxygenase-2 with PET—Synthesis, Triage, and Radiolabeling |
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