Purpose GSK2647544 is a potent and specific inhibitor of lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ), which was in development as a potential treatment for Alzheimer’s disease (AD). In order to refine therapeutic dose predictions and confirm brain penetration, a radiolabelled form of the inhibitor, 18 FGSK2647544, was manufactured for use in a positron emission tomography (PET) biodistribution study. Procedures 18 FGSK2647544 was produced using a novel, copper iodide (Cu(I)) mediated, 18 Ftrifluoromethylation methodology. Healthy male subjects ( n  = 4, age range 34–42) received an oral dose of unlabelled GSK2647544 (100 mg) and after 2 h an intravenous (iv) injection of 18 FGSK2647544 (average injected activity and mass were 106 ± 47 MBq and 179 ± 55 μg, respectively) followed by dynamic PET scans for 120 min. Defined regions of interest (ROI) throughout the brain were used to obtain regional time-activity curves (TACs) and compartmental modelling analysis used to estimate the primary outcome measure, whole brain volume of distribution (V T ). Secondary PK and safety endpoints were also recorded. Results PET dynamic data were successfully obtained from all four subjects and there were no clinically significant variations of the safety endpoints. Inspection of the TACs indicated a relatively homogenous uptake of 18 FGSK2647544 across all the ROIs examined. The mean whole brain V T was 0.56 (95 % CI, 0.41–0.72). Secondary PK parameters, C max (geometric mean) and T max (median), were 354 ng/ml and 1.4 h, respectively. Metabolism of GSK2647544 was relatively consistent across subjects, with 20–40 % of the parent compound 18 FGSK2647544 present after 120 min. Conclusions The study provides evidence that GSK2647544 is able to cross the blood brain barrier in healthy male subjects leading to a measurable brain exposure. The administered doses of GSK2647544 were well tolerated. Exploratory modelling suggested that a twice-daily dose of 102 mg, at steady state, would provide ~80 % trough inhibition of brain Lp-PLA 2 activity. Trial Registration Clintrials.gov: NCT01924858.