Abstract
PurposeGSK2647544 is a potent and specific inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2), 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, [18F]GSK2647544, was manufactured for use in a positron emission tomography (PET) biodistribution study.Procedures[18F]GSK2647544 was produced using a novel, copper iodide (Cu(I)) mediated, [18F]trifluoromethylation 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 [18F]GSK2647544 (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 (VT). Secondary PK and safety endpoints were also recorded.ResultsPET 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 [18F]GSK2647544 across all the ROIs examined. The mean whole brain VT was 0.56 (95 % CI, 0.41–0.72). Secondary PK parameters, Cmax (geometric mean) and Tmax (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 [18F]GSK2647544 present after 120 min.ConclusionsThe 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-PLA2 activity.Trial RegistrationClintrials.gov: NCT01924858.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that accounts for ~60–70 % of 947.5 million people affected worldwide by dementia [1]
The study provides evidence that GSK2647544 is able to cross the blood brain barrier in healthy male subjects leading to a measurable brain exposure
Lipoprotein-associated phospholipase A2 (Lp-PLA2) is primarily secreted by monocyte-derived macrophages and its expression is upregulated during inflammation [5]
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that accounts for ~60–70 % of 947.5 million people affected worldwide by dementia [1]. The disease is characterised neuropathologically by the formation of amyloid-beta containing senile plaques and tau containing neurofibrillary tangles and clinically by cognitive deficits that over time result in profound cognitive and functional impairment [2]. Lipoprotein-associated phospholipase A2 (Lp-PLA2), known as plasma platelet activating factor acetylhydrolase (PAF-AH), is a member of the phospholipase A2 superfamily of enzymes [4]. Lp-PLA2 is primarily secreted by monocyte-derived macrophages and its expression is upregulated during inflammation [5]. Lp-PLA2 circulates in plasma as a complex with low-density lipoprotein (LDL) and, to a lesser extent, with high-density lipoprotein (HDL) and lipoprotein(a) [5, 6]. Lp-PLA2 has been studied extensively as a marker of cardiovascular risk, and inhibitors of the enzyme were initially developed to counter the role of products derived from oxidised lowdensity lipoproteins in driving the vascular inflammation [6]
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