3-Substituted 1,5-Diaryl-1H-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 H -1,2,4-triazoles were prepared as prospective COX-1 PET radioligands. From this set, three 1,5-(4-methoxyphenyl)-1 H -1,2,4-triazoles, carrying a 3-methoxy ( 5 ), 3-(1,1,1-trifluoroethoxy) ( 20 ), or 3-fluoromethoxy substituent ( 6 ), 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 ( t 1/2 = 20.4 min) or fluorine-18 ( t 1/2 = 109.8 min). Methods were developed for producing [ 11 C]5, [ 11 C]20, and [ d 2 - 18 F] 6 from hydroxy precursors in a form ready for intravenous injection for prospective evaluation in monkey with PET.