3‑Substituted 1,5-Diaryl‑1<i>H</i>‑1,2,4-triazoles as Prospective PET Radioligands for Imaging Brain COX‑1 in Monkey. Part 1: Synthesis and Pharmacology

Cyclooxygenase-1 (COX-1) is a key enzyme in the biosynthesis of proinflammatory thromboxanes and prostaglandins and is found in glial and neuronal cells within brain. COX-1 expression is implicated in numerous neuroinflammatory states. We aim to find a direct-acting positron emission tomography (PET) radioligand for imaging COX-1 in human brain as a potential biomarker of neuroinflammation and for serving as a tool in drug development. Seventeen 3-substituted 1,5-diaryl-1<i>H</i>-1,2,4-triazoles were prepared as prospective COX-1 PET radioligands. From this set, three 1,5-(4-methoxyphenyl)-1<i>H</i>-1,2,4-triazoles, carrying a 3-methoxy (<b>5</b>), 3-(1,1,1-trifluoroethoxy) (<b>20</b>), or 3-fluoromethoxy substituent (<b>6</b>), were selected for radioligand development, based mainly on their high affinities and selectivities for inhibiting human COX-1, absence of carboxyl group, moderate computed lipophilicities, and scope for radiolabeling with carbon-11 (<i>t</i><sub>1/2</sub> = 20.4 min) or fluorine-18 (<i>t</i><sub>1/2</sub> = 109.8 min). Methods were developed for producing <b>[<sup>11</sup>C]­5</b>, <b>[<sup>11</sup>C]­20</b>, and [<i>d</i><sub>2</sub>-<sup>18</sup>F]<b>6</b> from hydroxy precursors in a form ready for intravenous injection for prospective evaluation in monkey with PET.