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Deuteration versus ethylation – strategies to improve the metabolic fate of an (18)F-labeled celecoxib derivative

The inducible isoenzyme cyclooxygenase-2 (COX-2) is closely associated with chemo-/radioresistance and poor prognosis of solid tumors. Therefore, COX-2 represents an attractive target for functional characterization of tumors by positron emission tomography (PET). In this study, the celecoxib deriva...

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Detalles Bibliográficos
Autores principales: Laube, Markus, Gassner, Cemena, Neuber, Christin, Wodtke, Robert, Ullrich, Martin, Haase-Kohn, Cathleen, Löser, Reik, Köckerling, Martin, Kopka, Klaus, Kniess, Torsten, Hey-Hawkins, Evamarie, Pietzsch, Jens
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society of Chemistry 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9057277/
https://www.ncbi.nlm.nih.gov/pubmed/35517533
http://dx.doi.org/10.1039/d0ra04494f
Descripción
Sumario:The inducible isoenzyme cyclooxygenase-2 (COX-2) is closely associated with chemo-/radioresistance and poor prognosis of solid tumors. Therefore, COX-2 represents an attractive target for functional characterization of tumors by positron emission tomography (PET). In this study, the celecoxib derivative 3-([(18)F]fluoromethyl)-1-[4-(methylsulfonyl)phenyl]-5-(p-tolyl)-1H-pyrazole ([(18)F]5a) was chosen as a lead compound having a reported high COX-2 inhibitory potency and a potentially low carbonic anhydrase binding tendency. The respective deuterated analog [D(2),(18)F]5a and the fluoroethyl-substituted derivative [(18)F]5b were selected to study the influence of these modifications with respect to COX inhibition potency in vitro and metabolic stability of the radiolabeled tracers in vivo. COX-2 inhibitory potency was found to be influenced by elongation of the side chain but, as expected, not by deuteration. An automated radiosynthesis comprising (18)F-fluorination and purification under comparable conditions provided the radiotracers [(18)F]5a,b and [D(2),(18)F]5a in good radiochemical yields (RCY) and high radiochemical purity (RCP). Biodistribution and PET studies comparing all three compounds revealed bone accumulation of (18)F-activity to be lowest for the ethyl derivative [(18)F]5b. However, the deuterated analog [D(2),(18)F]5a turned out to be the most stable compound of the three derivatives studied here. Time-dependent degradation of [(18)F]5a,b and [D(2),(18)F]5a after incubation in murine liver microsomes was in accordance with the data on metabolism in vivo. Furthermore, metabolites were identified based on UPLC-MS/MS.