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

• Published in: Molecules (Basel, Switzerland) Switzerland), 2018-11, Vol.23 (11), p.2850
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Anti-inflammatory agents; Arachidonic acid; Carbon; carbon-11; COX-2; COX-2 inhibitors; Cyclooxygenase-1; Cyclooxygenase-2; Drug development; Emitters; Enzymes; Fluorine; Fluorine isotopes; fluorine-18; High-performance liquid chromatography; In vivo methods and tests; Inflammation; Inhibitors; Intravenous administration; Iodomethane; Labeling; Ligands; Liquid chromatography; Nonsteroidal anti-inflammatory drugs; Positron emission; Positron emission tomography; Prostaglandins; Pyrimidines; Radioisotopes; radioligand; Tomography
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules23112850

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.