Investigation of the Brain Biodistribution of the Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Inhibitor [18F]GSK2647544 in Healthy Male Subjects

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.Electronic supplementary materialThe online version of this article (doi:10.1007/s11307-016-0982-5) contains supplementary material, which is available to authorized users.

Small-molecule inhibitors as potential therapeutics and as tools to understand the role of phospholipases A2

“…According to the results, GSK2647544 is able to cross the blood brain barrier and enter the human brain. An exploratory analysis of the data indicated that a dose of 102 mg, twice daily would be sufficient to in-hibit~80% brain LpPLA 2 [126].…”

Lipoprotein‐associated phospholipase A2: The story continues

“…Furthermore, GSK2647544 could likely penetrate into the brains of preclinical species, which was verified by positron emission tomography biodistribution studies using [ 18 F] radiolabeled GSK2647544. This clinical trial also found that a twice‐daily dose of 102 mg generated approximately 80% trough inhibition of brain Lp‐PLA2 activity at steady state according to an exploratory analysis . Taken together, preclinical and preliminarily clinical studies showed that GSK2647544 acted as a useful tool for determining the effects of brain Lp‐PLA2 inhibition.…”

“…This clinical trial also found that a twice-daily dose of 102 mg generated approximately 80% trough inhibition of brain Lp-PLA2 activity at steady state according to an exploratory analysis. 255 Taken together, preclinical and preliminarily clinical studies showed that GSK2647544 acted as a useful tool for determining the effects of brain Lp-PLA2 inhibition. However, another study reported that GSK2647544 might be a moderate to strong CYP3A4 inhibitor, suggesting potential adverse drug-drug interaction.…”

Synthesis and Derivatization of 1,1‐[18F]Difluorinated Alkenes

“…While carbon-based perfluorinated functional groups are commonplace in numerous pharmaceuticals,a grochemicals and, materials, 18 F-perfluorinated motifs are seldom used in PET imaging. [5,6] This discrepancy is ac onsequence of the non-trivial nature of the radiochemical synthesis of these 18 Fperfluorinated functional groups,c oupled with the isotopic dilution with fluorine-19 that is usually observed. This results in products of low molar activity (A m ), potentially limiting their application.…”

“…To test this hypothesis,t he initial studies began by synthesizing arange of fluoroalkenyl(aryl)iodonium triflates, bearing the 2-thienyl, mesityl, and 4-methoxyphenyl groups, [19] which are amongst the most commonly employed arenes for the 18 F-fluorination of diaryliodonium salts (Table 1). It was found that the use of (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl (TEMPO) was critical for the reaction to proceed in good radiochemical purity (RCP;T able 1, entries 4,6,7,9). [20] Thef luoroalkenyl(4-methoxyphenyl)iodonium triflate was found to give the highest RCP of 51 AE 12 % (n = 3), in acetonitrile at 85 8 8C( [21] however, the application of their conditions in this instance was not beneficial (Table 1, entry 3).…”