Format

Send to

Choose Destination
Mol Imaging Biol. 2017 Feb;19(1):153-161. doi: 10.1007/s11307-016-0982-5.

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

Author information

1
Imanova Limited, Burlington Danes Building, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
2
WuXi Clinical Development Service, 19th Floor, Building A, FuXing Plaza, 388 Ma Dang Road, Shanghai, 200025, China.
3
GlaxoSmithKline, Neurosciences, 917 Halei Road, Zhangjiang Hi-tech Park, Pudong, Shanghai, 201203, China.
4
AstraZeneca UK Limited, Melbourn Science Park, Royston, Herts, SG8 6HB, UK.
5
GlaxoSmithKline, Neurosciences, Gunnels Wood Road, Stevenage, SG1 2NY, UK.
6
UCB Biosciences Inc, PO Box 110167, Research Triangle Park, NC, 27709, USA.
7
GlaxoSmithKline, Neurosciences, Clinical Unit Cambridge, Addenbrooke's Hospital, Cambridge, CB2 0GG, UK. andrew.2.lockhart@gsk.com.

Abstract

PURPOSE:

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.

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.

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 [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.

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-PLA2 activity.

TRIAL REGISTRATION:

Clintrials.gov: NCT01924858.

KEYWORDS:

Alzheimer’s disease; Biodistribution; GSK2647544; Lp-PLA2; PET; Positron emission tomography

PMID:
27402093
PMCID:
PMC5209404
DOI:
10.1007/s11307-016-0982-5
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

A. Lockhart, M. Buraglio, S. Shabbir Y. Xu, K. Wu, C. Guan and R. Fong were/are employees of GlaxoSmithKline and receive payment and stock remuneration as part of that employment but have no other financial interests or conflicts of interest. M. Huiban, EA. Rabiner, AP. Brown, Y. Lewis, C. Coello and J. Passchier were/are employees of Imanova Limited at the time of the study. M. Huiban, EA. Rabiner, AP. Brown, Y. Lewis and J. Passchier were former employees of GlaxoSmithKline and have received payment and stock remuneration as part of that employment but have no other financial interests or conflicts of interest. C. Coello has no additional competing interest. AP. Brown is currently an employee of AstraZeneca UK Limited. GlaxoSmithKline provided the funding for the design and conduct of this study, the collection, management, analysis and interpretation of the data and coordinated the preparation and review of the manuscript. Research Involving Human Participants and/or Animals All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the principles of the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Informed Consent Informed consent was obtained from all individual participants included in the study. Animal Research All studies were conducted in accordance with the GlaxoSmithKline Policy on the Care, Welfare, and Treatment of Laboratory Animals and additionally approved by the institutional animal care and use committee (IACUC) and national guidelines for the care and use of animals.

Supplemental Content

Full text links

Icon for Springer Icon for PubMed Central
Loading ...
Support Center