Deuteration Ethylation - Strategies to Improve the Metabolic Fate of an F-labeled Celecoxib Derivative

Overview

Journal RSC Adv

Publisher Royal Society of Chemistry

Specialty Chemistry

Date 2022 May 6

PMID 35517533

Authors

Markus Laube

Cemena Gassner

Christin Neuber

Robert Wodtke

Martin Ullrich

Cathleen Haase-Kohn

Reik Loser

Martin Kockerling

Klaus Kopka

Torsten Kniess

Evamarie Hey-Hawkins

Jens Pietzsch

Affiliations

Soon will be listed here.

Abstract

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-([F]fluoromethyl)-1-[4-(methylsulfonyl)phenyl]-5-(-tolyl)-1-pyrazole ([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,F]5a and the fluoroethyl-substituted derivative [F]5b were selected to study the influence of these modifications with respect to COX inhibition potency and metabolic stability of the radiolabeled tracers . 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 F-fluorination and purification under comparable conditions provided the radiotracers [F]5a,b and [D,F]5a in good radiochemical yields (RCY) and high radiochemical purity (RCP). Biodistribution and PET studies comparing all three compounds revealed bone accumulation of F-activity to be lowest for the ethyl derivative [F]5b. However, the deuterated analog [D,F]5a turned out to be the most stable compound of the three derivatives studied here. Time-dependent degradation of [F]5a,b and [D,F]5a after incubation in murine liver microsomes was in accordance with the data on metabolism . Furthermore, metabolites were identified based on UPLC-MS/MS.

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