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EJNMMI Research
Published in: EJNMMI Research 1/2017

Open Access 01-12-2017 | Original research

Design, synthesis and evaluation in an LPS rodent model of neuroinflammation of a novel 18F-labelled PET tracer targeting P2X7

Authors: Enrico Raffaele Fantoni, Diego Dal Ben, Simonetta Falzoni, Francesco Di Virgilio, Simon Lovestone, Antony Gee

Published in: EJNMMI Research | Issue 1/2017

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Abstract

Background

The P2X7 receptor has been shown to play a fundamental role in the initiation and sustenance of the inflammatory cascade. The development of a novel fluorine-18 PET tracer superior and with a longer half-life to those currently available is a promising step towards harnessing the therapeutic and diagnostic potential offered by this target. Inspired by the known antagonist A-804598, the present study outlines the design via molecular docking, synthesis and biological evaluation of the novel P2X7 tracer [18F]EFB. The tracer was radiolabelled via a three-step procedure, in vitro binding assessed in P2X7-transfected HEK293 and in B16 cells by calcium influx assays and an initial preclinical evaluation was performed in a lipopolysaccharide (LPS)-injected rat model of neuroinflammation.

Results

The novel tracer [18F]EFB was synthesised in 210 min in 3–5% decay-corrected radiochemical yield (DC RCY), >99% radiochemical purity (RCP) and >300 GBq/μmol and fully characterised. Functional assays showed that the compound binds with nM K i to human, rat and mouse P2X7 receptors. In vivo, [18F]EFB displayed a desirable distribution profile, and while it showed low blood–brain barrier penetration, brain uptake was quantifiable and displayed significantly higher mean longitudinal uptake in inflamed versus control rat CNS regions.

Conclusions

[18F]EFB demonstrates strong in vitro affinity to human and rodent P2X7 and limited yet quantifiable BBB penetration. Considering the initial promising in vivo data in an LPS rat model with elevated P2X7 expression, this work constitutes an important step in the development of a radiotracer useful for the diagnosis and monitoring of clinical disorders with associated neuroinflammatory processes.
Appendix
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Metadata
Title
Design, synthesis and evaluation in an LPS rodent model of neuroinflammation of a novel 18F-labelled PET tracer targeting P2X7
Authors
Enrico Raffaele Fantoni
Diego Dal Ben
Simonetta Falzoni
Francesco Di Virgilio
Simon Lovestone
Antony Gee
Publication date
01-12-2017
Publisher
Springer Berlin Heidelberg
Published in
EJNMMI Research / Issue 1/2017
Electronic ISSN: 2191-219X
DOI
https://doi.org/10.1186/s13550-017-0275-2

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