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. 2018 Nov 2;23(11):2850.
doi: 10.3390/molecules23112850.

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

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Free PMC article

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

Michelle Y Cortes-Salva et al. Molecules. .
Free PMC article

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 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.

Keywords: COX-2; carbon-11; fluorine-18; radioligand.

Conflict of interest statement

The authors declare no competing financial interest.

Figures

Chart 1
Chart 1
Some features of former candidate COX-2 positron emission tomography (PET) radioligands. Data are from the literature cited in the text, except for clogD values which were computed from 2-dimensional structure with Pallas software (see Experimental).
Scheme 1
Scheme 1
Syntheses of known and potential inhibitors, and precursors for radiolabeling. Reagents and conditions: (i) for 12, 13, and 15, RX, NaH, THF, RT, 3 h; for 14 (R = SEt) and 16 (R = SMe): RNa, THF 50 °C, 3 h. (ii) thiophen-2-ylmethanamine, NEt3, MeCN, 5 d. (iii) thiophen-2ylmethanamine, Cs2CO3, DMF, 160 °C, 100 W, 25 min. (iv) benzylamine, NEt3, MeCN, 5 d. (v) benzylamine, Cs2CO3, DMF, 160 °C, 100 W, 25 min. (vi) BippyPhos (8 mol %), Pd2dba3 (2 mol %), CsOH·H2O, 100 °C, dioxane, 20 h. (vii) FCH2I, K2CO3, DMF, 40 °C, 4 h. (viii) NaH, DMF, MeI, RT, 24 h. (ix) KF, 18-crown-6, MeCN, RT, 24 h.
Scheme 2
Scheme 2
Radiosyntheses of [11C]17, [18F]20, and [18F]27. Reagents and conditions: (i) [11C]CH3I, DMF, TBAH, RT, 5 min. (ii) [18F]FCH2CH2Br, DMF, Cs2CO3, 18-crown-6, 110 °C, 15 min. (iii) [18F]FCD2Br, Cs2CO3, 18-crown-6, 110 °C, 15 min.
Figure 1
Figure 1
HPLC radiochromatograms for the separation of the radioligands [11C]17, [18F]20, and [d218F]27 (panels A, C, and E, respectively) and the respective chromatograms for HPLC analyses of the formulated radioligands (panels B, D, and F, respectively).

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