3-Substituted 1,5-Diaryl-1 H-1,2,4-triazoles as Prospective PET Radioligands for Imaging Brain COX-1 in Monkey. Part...

In our preceding paper (Part 1), we identified three 1,5-bis-diaryl-1,2,4-triazole-based compounds that merited evaluation as potential positron emission tomography (PET) radioligands for selectively imaging cyclooxygenase-1 (COX-1) in monkey and human brain, namely, 1,5-bis(4-methoxyphenyl)-3-(alkoxy)-1 H-1,2,4-triazoles bearing a 3-methoxy (PS1), a 3-(2,2,2-trifluoroethoxy) (PS13), or a 3-fluoromethoxy substituent (PS2). PS1 and PS13 were labeled from phenol precursors by O-¹¹C-methylation with [¹¹C]iodomethane and PS2 by O-¹⁸F-fluoroalkylation with [²H₂,¹⁸F]fluorobromomethane. Here, we evaluated these PET radioligands in monkey. All three radioligands gave moderately high uptake in brain, although [²H₂,¹⁸F]PS2 also showed undesirable radioactivity uptake in skull. [¹¹C]PS13 was selected for further evaluation, mainly based on more favorable brain kinetics than [¹¹C]PS1. Pharmacological preblock experiments showed that about 55% of the radioactivity uptake in brain was specifically bound to COX-1. An index of enzyme density, V_T, was well identified from serial brain scans and from the concentrations of parent radioligand in arterial plasma. In addition, V_T values were stable within 80 min, suggesting that brain uptake was not contaminated by radiometabolites. [¹¹C]PS13 successfully images and quantifies COX-1 in monkey brain, and merits further investigation for imaging COX-1 in monkey models of neuroinflammation and in healthy human subjects.