Identification of the allosteric P2X7 receptor antagonist [11C]SMW139 as a PET tracer of microglial activation

Bieneke Janssen; Danielle J. Vugts; Shane M. Wilkinson; Dieter Ory; Sylvie Chalon; Jeroen J.M. Hoozemans; Robert C. Schuit; Wissam Beaino; Esther J.M. Kooijman; Johan Van Den Hoek; Mansoor Chishty; Aurélie Doméné; Anke Van Der Perren; Alessandro Villa; Adriana Maggi; Ger T. Molenaar; Uta Funke; Rostislav V. Shevchenko; Veerle Baekelandt; Guy Bormans; Adriaan A. Lammertsma; Michael Kassiou; Albert D. Windhorst

doi:10.1038/s41598-018-24814-0

Identification of the allosteric P2X₇ receptor antagonist [¹¹C]SMW139 as a PET tracer of microglial activation

Bieneke Janssen^*
, Danielle J. Vugts
, Shane M. Wilkinson
, Dieter Ory
, Sylvie Chalon
, Jeroen J.M. Hoozemans
, Robert C. Schuit
, Wissam Beaino
, Esther J.M. Kooijman
, Johan Van Den Hoek
, Mansoor Chishty
, Aurélie Doméné
, Anke Van Der Perren
, Alessandro Villa
, Adriana Maggi
, Ger T. Molenaar
, Uta Funke
, Rostislav V. Shevchenko
, Veerle Baekelandt
, Guy Bormans

Adriaan A. Lammertsma, Michael Kassiou, Albert D. Windhorst

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

The P2X₇ receptor plays a significant role in microglial activation, and as a potential drug target, the P2X₇ receptor is also an interesting target in positron emission tomography. The current study aimed at the development and evaluation of a potent tracer targeting the P2X₇ receptor, to which end four adamantanyl benzamide analogues with high affinity for the human P2X₇ receptor were labelled with carbon-11. All four analogues could be obtained in excellent radiochemical yield and high radiochemical purity and molar activity, and all analogues entered the rat brain. [¹¹C]SMW139 showed the highest metabolic stability in rat plasma, and showed high binding to the hP2X₇ receptor in vivo in a hP2X₇ receptor overexpressing rat model. Although no significant difference in binding of [¹¹C]SMW139 was observed between post mortem brain tissue of Alzheimer's disease patients and that of healthy controls in in vitro autoradiography experiments, [¹¹C]SMW139 could be a promising tracer for P2X₇ receptor imaging using positron emission tomography, due to high receptor binding in vivo in the hP2X₇ receptor overexpressing rat model. However, further investigation of both P2X₇ receptor expression and binding of [¹¹C]SMW139 in other neurological diseases involving microglial activation is warranted.

Original language	English
Article number	6580
Journal	Scientific Reports
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41598-018-24814-0
Publication status	Published - 1 Dec 2018

Funding

The research leading to these results has received funding from the European Union’s Seventh Framework Programme (FP7/2007–2013) under grant agreement n° HEALTH-F2-2011-278850 (INMiND). Dieter Ory and Anke Van der Perren are supported by a postdoctoral mandate of the Research Foundation Flanders (FWO). Viral vectors were engineered and produced by the Leuven Viral Vector Core (Leuven, Belgium).

Funders	Funder number
INMiND
Fonds Wetenschappelijk Onderzoek
European Commission
Seventh Framework Programme	278850, HEALTH-F2-2011-278850

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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Cite this

Janssen, B., Vugts, D. J., Wilkinson, S. M., Ory, D., Chalon, S., Hoozemans, J. J. M., Schuit, R. C., Beaino, W., Kooijman, E. J. M., Van Den Hoek, J., Chishty, M., Doméné, A., Van Der Perren, A., Villa, A., Maggi, A., Molenaar, G. T., Funke, U., Shevchenko, R. V., Baekelandt, V., ... Windhorst, A. D. (2018). Identification of the allosteric P2X₇ receptor antagonist [¹¹C]SMW139 as a PET tracer of microglial activation. Scientific Reports, 8(1), Article 6580. https://doi.org/10.1038/s41598-018-24814-0

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title = "Identification of the allosteric P2X7 receptor antagonist [11C]SMW139 as a PET tracer of microglial activation",

abstract = "The P2X7 receptor plays a significant role in microglial activation, and as a potential drug target, the P2X7 receptor is also an interesting target in positron emission tomography. The current study aimed at the development and evaluation of a potent tracer targeting the P2X7 receptor, to which end four adamantanyl benzamide analogues with high affinity for the human P2X7 receptor were labelled with carbon-11. All four analogues could be obtained in excellent radiochemical yield and high radiochemical purity and molar activity, and all analogues entered the rat brain. [11C]SMW139 showed the highest metabolic stability in rat plasma, and showed high binding to the hP2X7 receptor in vivo in a hP2X7 receptor overexpressing rat model. Although no significant difference in binding of [11C]SMW139 was observed between post mortem brain tissue of Alzheimer's disease patients and that of healthy controls in in vitro autoradiography experiments, [11C]SMW139 could be a promising tracer for P2X7 receptor imaging using positron emission tomography, due to high receptor binding in vivo in the hP2X7 receptor overexpressing rat model. However, further investigation of both P2X7 receptor expression and binding of [11C]SMW139 in other neurological diseases involving microglial activation is warranted.",

author = "Bieneke Janssen and Vugts, \{Danielle J.\} and Wilkinson, \{Shane M.\} and Dieter Ory and Sylvie Chalon and Hoozemans, \{Jeroen J.M.\} and Schuit, \{Robert C.\} and Wissam Beaino and Kooijman, \{Esther J.M.\} and \{Van Den Hoek\}, Johan and Mansoor Chishty and Aur{\'e}lie Dom{\'e}n{\'e} and \{Van Der Perren\}, Anke and Alessandro Villa and Adriana Maggi and Molenaar, \{Ger T.\} and Uta Funke and Shevchenko, \{Rostislav V.\} and Veerle Baekelandt and Guy Bormans and Lammertsma, \{Adriaan A.\} and Michael Kassiou and Windhorst, \{Albert D.\}",

year = "2018",

month = dec,

day = "1",

doi = "10.1038/s41598-018-24814-0",

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Janssen, B, Vugts, DJ, Wilkinson, SM, Ory, D, Chalon, S, Hoozemans, JJM, Schuit, RC, Beaino, W, Kooijman, EJM, Van Den Hoek, J, Chishty, M, Doméné, A, Van Der Perren, A, Villa, A, Maggi, A, Molenaar, GT, Funke, U, Shevchenko, RV, Baekelandt, V, Bormans, G, Lammertsma, AA, Kassiou, M & Windhorst, AD 2018, 'Identification of the allosteric P2X₇ receptor antagonist [¹¹C]SMW139 as a PET tracer of microglial activation', Scientific Reports, vol. 8, no. 1, 6580. https://doi.org/10.1038/s41598-018-24814-0

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T1 - Identification of the allosteric P2X7 receptor antagonist [11C]SMW139 as a PET tracer of microglial activation

AU - Janssen, Bieneke

AU - Vugts, Danielle J.

AU - Wilkinson, Shane M.

AU - Ory, Dieter

AU - Chalon, Sylvie

AU - Hoozemans, Jeroen J.M.

AU - Schuit, Robert C.

AU - Beaino, Wissam

AU - Kooijman, Esther J.M.

AU - Van Den Hoek, Johan

AU - Chishty, Mansoor

AU - Doméné, Aurélie

AU - Van Der Perren, Anke

AU - Villa, Alessandro

AU - Maggi, Adriana

AU - Molenaar, Ger T.

AU - Funke, Uta

AU - Shevchenko, Rostislav V.

AU - Baekelandt, Veerle

AU - Bormans, Guy

AU - Lammertsma, Adriaan A.

AU - Kassiou, Michael

AU - Windhorst, Albert D.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - The P2X7 receptor plays a significant role in microglial activation, and as a potential drug target, the P2X7 receptor is also an interesting target in positron emission tomography. The current study aimed at the development and evaluation of a potent tracer targeting the P2X7 receptor, to which end four adamantanyl benzamide analogues with high affinity for the human P2X7 receptor were labelled with carbon-11. All four analogues could be obtained in excellent radiochemical yield and high radiochemical purity and molar activity, and all analogues entered the rat brain. [11C]SMW139 showed the highest metabolic stability in rat plasma, and showed high binding to the hP2X7 receptor in vivo in a hP2X7 receptor overexpressing rat model. Although no significant difference in binding of [11C]SMW139 was observed between post mortem brain tissue of Alzheimer's disease patients and that of healthy controls in in vitro autoradiography experiments, [11C]SMW139 could be a promising tracer for P2X7 receptor imaging using positron emission tomography, due to high receptor binding in vivo in the hP2X7 receptor overexpressing rat model. However, further investigation of both P2X7 receptor expression and binding of [11C]SMW139 in other neurological diseases involving microglial activation is warranted.

AB - The P2X7 receptor plays a significant role in microglial activation, and as a potential drug target, the P2X7 receptor is also an interesting target in positron emission tomography. The current study aimed at the development and evaluation of a potent tracer targeting the P2X7 receptor, to which end four adamantanyl benzamide analogues with high affinity for the human P2X7 receptor were labelled with carbon-11. All four analogues could be obtained in excellent radiochemical yield and high radiochemical purity and molar activity, and all analogues entered the rat brain. [11C]SMW139 showed the highest metabolic stability in rat plasma, and showed high binding to the hP2X7 receptor in vivo in a hP2X7 receptor overexpressing rat model. Although no significant difference in binding of [11C]SMW139 was observed between post mortem brain tissue of Alzheimer's disease patients and that of healthy controls in in vitro autoradiography experiments, [11C]SMW139 could be a promising tracer for P2X7 receptor imaging using positron emission tomography, due to high receptor binding in vivo in the hP2X7 receptor overexpressing rat model. However, further investigation of both P2X7 receptor expression and binding of [11C]SMW139 in other neurological diseases involving microglial activation is warranted.

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