Synthesis and Automated Labeling of [18F]Darapladib, a Lp-PLA2 Ligand, as Potential PET Imaging Tool of Atherosclerosis

Atherosclerosis and its associated clinical complications are major health issues in industrialized countries. Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) was demonstrated to play an important role in atherogenesis and to be a potential risk prediction factor of plaque rupture. Darapladib is one of the most potent Lp-PLA(2) inhibitors with an IC50 of 0.25 nM. Using its affinity for Lp-PLA(2), we describe herein the total synthesis of darapladib radiolabeling precursor and the automated radiolabeling process for positron emission tomography (PET) imaging via an arylboronate moiety. The tracer thus obtained was tested in a mouse model of atherosclerosis (ApoE KO) and compared with the widely used [F-18]fluorodeoxyglucose ([F-18]FDG) PET tracer, known to label metabolically active cells. [F-18]Darapladib showed a significant accumulation within mice aortic atheromatous plaques dissected out ex vivo compared to [F-18]FDG. Incubation of the radiotracer with human carotid samples showed a strong accumulation within the atherosclerotic plaques and supports its potential for use in PET imaging.