3‑Substituted 1,5-Diaryl‑1H‑1,2,4-triazoles as Prospective PET Radioligands for Imaging Brain COX‑1 in Monkey. Part 2: Selection and Evaluation of [11C]PS13 for Quantitative Imaging

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)-1H-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, VT, was well identified from serial brain scans and from the concentrations of parent radioligand in arterial plasma. In addition, VT 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.