Design, synthesis and evaluation in an LPS rodent model of neuroinflammation of a novel 18F-labelled PET tracer targeting P2X7Reportar como inadecuado

Design, synthesis and evaluation in an LPS rodent model of neuroinflammation of a novel 18F-labelled PET tracer targeting P2X7 - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

EJNMMI Research

, 7:31

First Online: 04 April 2017Received: 14 November 2016Accepted: 08 March 2017DOI: 10.1186-s13550-017-0275-2

Cite this article as: Fantoni, E., Dal Ben, D., Falzoni, S. et al. EJNMMI Res 2017 7: 31. doi:10.1186-s13550-017-0275-2


BackgroundThe 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 FEFB. 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.

ResultsThe novel tracer FEFB 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 Ki to human, rat and mouse P2X7 receptors. In vivo, FEFB 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.

ConclusionsFEFB 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.

KeywordsP2X7 F-18 LPS EFB Radiosynthesis Molecular modelling Electronic supplementary materialThe online version of this article doi:10.1186-s13550-017-0275-2 contains supplementary material, which is available to authorized users.

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


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