TY - JOUR
T1 - 3-Substituted 1,5-Diaryl-1 H-1,2,4-triazoles as Prospective PET Radioligands for Imaging Brain COX-1 in Monkey. Part 2
T2 - Selection and Evaluation of [11C]PS13 for Quantitative Imaging
AU - Shrestha, Stal
AU - Singh, Prachi
AU - Cortes-Salva, Michelle Y.
AU - Jenko, Kimberly J.
AU - Ikawa, Masamichi
AU - Kim, Min Jeong
AU - Kobayashi, Masato
AU - Morse, Cheryl L.
AU - Gladding, Robert L.
AU - Liow, Jeih San
AU - Zoghbi, Sami S.
AU - Fujita, Masahiro
AU - Innis, Robert B.
AU - Pike, Victor W.
N1 - Funding Information:
*Phone: 301 594 5986. Fax: 301 480 5112. E-mail: pikev@mail. nih.gov. ORCID Victor W. Pike: 0000-0001-9032-2553 Author Contributions S.S., M.I., M.-J.K., M.K., R.L.G., M.F., and J.-S.L.: PET imaging and analysis; P.S., M.Y.C.-S. and C.L.M.: compound synthesis, radiochemistry, and radioligand production; S.S.Z. and K.J.J.: metabolite analysis, log D, and fP measurements; R.B.I. and V.W.P.: concept and design of study. All authors contributed to writing of the paper (overseen by R.B.I. and V.W.P.). Funding This study was supported by the Intramural Research Program of the National Institute of Health (NIH) (Projects ZIA-MH002852 and ZIA-MH002793). Notes The authors declare no competing financial interest.
Publisher Copyright:
© This article not subject to U.S. Copyright. Published 2018 by the American Chemical Society.
PY - 2018/11/21
Y1 - 2018/11/21
N2 - 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.
AB - 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.
KW - COX-1
KW - PET
KW - brain
KW - carbon-11
KW - fluorine-18
KW - radioligand
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U2 - 10.1021/acschemneuro.8b00103
DO - 10.1021/acschemneuro.8b00103
M3 - Article
C2 - 29792035
AN - SCOPUS:85047616073
SN - 1948-7193
VL - 9
SP - 2620
EP - 2627
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
IS - 11
ER -