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 derivative 3-([ 18 F]fluoromethyl)-1-[4-(methylsulfonyl)phenyl]-5-( p -tolyl)-1 H -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.