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Molecules 2018, 23(11), 2850;

2-(4-Methylsulfonylphenyl)pyrimidines as Prospective Radioligands for Imaging Cyclooxygenase-2 with PET—Synthesis, Triage, and Radiolabeling

Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA
Author to whom correspondence should be addressed.
Academic Editor: Anne Roivainen
Received: 11 October 2018 / Revised: 26 October 2018 / Accepted: 27 October 2018 / Published: 2 November 2018
(This article belongs to the Section Medicinal Chemistry)
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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. View Full-Text
Keywords: COX-2; radioligand; carbon-11; fluorine-18 COX-2; radioligand; carbon-11; fluorine-18

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Cortes-Salva, M.Y.; Shrestha, S.; Singh, P.; Morse, C.L.; Jenko, K.J.; Montero Santamaria, J.A.; Zoghbi, S.S.; Innis, R.B.; Pike, V.W. 2-(4-Methylsulfonylphenyl)pyrimidines as Prospective Radioligands for Imaging Cyclooxygenase-2 with PET—Synthesis, Triage, and Radiolabeling. Molecules 2018, 23, 2850.

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