title: Investigation of the Brain Biodistribution of the Lipoprotein-Associated Phospholipase A2(Lp-PLA2) Inhibitor [18F]GSK2647544 in Healthy Male Subjects.
abstract: GSK2647544 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.
  
  
  
  [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.
  
  
  
  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 [18F]GSK2647544 across all the ROIs examined. The mean whole brain VTwas 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.
  
  
  
  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-PLA2activity.
  
  
  
  Clintrials.gov: NCT01924858.
authors.affiliation: Imanova Limited, Burlington Danes Building, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
authors.forename: Mickael
authors.initials: M
authors.lastname: Huiban
authors.affiliation: Imanova Limited, Burlington Danes Building, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Coello
authors.affiliation: WuXi Clinical Development Service, 19th Floor, Building A, FuXing Plaza, 388 Ma Dang Road, Shanghai, 200025, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Wu
authors.affiliation: GlaxoSmithKline, Neurosciences, 917 Halei Road, Zhangjiang Hi-tech Park, Pudong, Shanghai, 201203, China.
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Imanova Limited, Burlington Danes Building, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Lewis
authors.affiliation: AstraZeneca UK Limited, Melbourn Science Park, Royston, Herts, SG8 6HB, UK.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Brown
authors.affiliation: GlaxoSmithKline, Neurosciences, Gunnels Wood Road, Stevenage, SG1 2NY, UK.
authors.forename: Mauro
authors.initials: M
authors.lastname: Buraglio
authors.affiliation: GlaxoSmithKline, Neurosciences, 917 Halei Road, Zhangjiang Hi-tech Park, Pudong, Shanghai, 201203, China.
authors.forename: Chenbing
authors.initials: C
authors.lastname: Guan
authors.affiliation: GlaxoSmithKline, Neurosciences, Gunnels Wood Road, Stevenage, SG1 2NY, UK.
authors.forename: Shaila
authors.initials: S
authors.lastname: Shabbir
authors.affiliation: UCB Biosciences Inc, PO Box 110167, Research Triangle Park, NC, 27709, USA.
authors.forename: Regan
authors.initials: R
authors.lastname: Fong
authors.affiliation: Imanova Limited, Burlington Danes Building, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
authors.forename: Jan
authors.initials: J
authors.lastname: Passchier
authors.affiliation: Imanova Limited, Burlington Danes Building, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
authors.forename: Eugenii A
authors.initials: EA
authors.lastname: Rabiner
authors.affiliation: GlaxoSmithKline, Neurosciences, Clinical Unit Cambridge, Addenbrooke's Hospital, Cambridge, CB2 0GG, UK. andrew.2.lockhart@gsk.com.
authors.forename: Andrew
authors.initials: A
authors.lastname: Lockhart
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000328:Adult; D000818:Animals; D001921:Brain / Q000378:metabolism*; D005462:Fluorine Radioisotopes / Q000737:chemistry*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008297:Male; D051379:Mice; D008875:Middle Aged; D010647:Phenyl Ethers / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011744:Pyrimidinones / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051381:Rats; D013997:Time Factors; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D005462:Fluorine Radioisotopes; C000615596:GSK2647544; D010647:Phenyl Ethers; D011744:Pyrimidinones; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase
keywords: Alzheimer’s disease; Biodistribution; GSK2647544; Lp-PLA2; PET; Positron emission tomography