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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
journal contribution
posted on 2018-05-23, 00:00 authored by Stal Shrestha, Prachi Singh, Michelle Y. Cortes-Salva, Kimberly J. Jenko, Masamichi Ikawa, Min-Jeong Kim, Masato Kobayashi, Cheryl L. Morse, Robert L. Gladding, Jeih-San Liow, Sami S. Zoghbi, Masahiro Fujita, Robert B. Innis, Victor W. PikeIn
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.