Synthesis and Preclinical Evaluation of F-Labeled Ketoprofen Methyl Esters for Cyclooxygenase-1 Imaging in Neuroinflammation.

Cyclooxygenase (COX) is a rate-limiting enzyme in the synthesis of proinflammatory prostanoids from arachidonic acid. In vivo imaging of COX by PET is a potentially powerful tool for assessing the inflammatory response to injury, infection, and disease. We previously reported on a promising PET probe for COX imaging, C-labeled ketoprofen methyl ester, which can detect COX-1 activation in models of neuroinflammation and neurodegenerative disorders. In the current study, we aimed to design a fluorine-substituted benzoyl group of ketoprofen (FKTP) and to evaluate its racemate and enantiomers (F-labeled ketoprofen methyl ester, [F]FKTP-Me) as PET proradiotracers, potential radiopharmaceuticals for in vivo PET study of COX-1. We performed nucleophilic aromatic F-fluorination to obtain the desired racemic radiolabeled probe, ()-[F]FKTP-Me, at a radiochemical yield of 11%-13%. Subsequent high-performance liquid chromatography separation with a chiral column yielded the desired enantiomerically pure ()- and ()-[F]FKTP-Me. We examined the in vivo properties of ()-, ()-, and ()-[F]FKTP-Me in PET studies using rats in which hemispheric inflammation was induced by intrastriatally injecting a lipopolysaccharide. Racemic ()-[F]FKTP-Me and enantiomeric ()- or ()-[F]FKTP-Me were synthesized with radiochemical and chemical purities of more than 99%. The metabolite analysis revealed that the racemic ()-[F]FKTP-Me crossed the blood-brain barrier and entered the brain, where it was subsequently hydrolyzed to its pharmacologically active acid form. PET images revealed a high accumulation of ()-, ()-, and ()-[F]FKTP in the inflamed regions in rat brain. Moreover, the accumulated radioactivity of ()-[F]FKTP-Me was higher than that of ()-[F]FKTP-Me and ()-[F]FKTP-Me, which was correlated with the stereospecific inhibitory activity of FKTP against COX-1. From the results of this study, we conclude that racemic ()-[F]FKTP-Me and its enantiomers could act as proradiotracers of neuroinflammation in rat brain by the association of their hydrolyzed acid forms with COX-1 in inflamed regions. In particular, ()-[F]FKTP-Me demonstrated suitable properties as a COX-1-specific probe in PET imaging of neuroinflammation.