Identification of the allosteric P2X7 receptor antagonist [11C]SMW139 as a PET tracer of microglial activation.
Creators
- Janssen, Bieneke1
- Vugts, Danielle J1
- Wilkinson, Shane M2
- Ory, Dieter3
- Chalon, Sylvie4
- Hoozemans, Jeroen JM5
- Schuit, Robert C1
- Beaino, Wissam1
- Kooijman, Esther JM1
- van den Hoek, Johan1
- Chishty, Mansoor6
- Doméné, Aurélie4
- Van der Perren, Anke7
- Villa, Alessandro8
- Maggi, Adriana8
- Molenaar, Ger T9
- Funke, Uta10
- Shevchenko, Rostislav V6
- Baekelandt, Veerle7
- Bormans, Guy3
- Lammertsma, Adriaan A1
- Kassiou, Michael2
- Windhorst, Albert D1
- 1. Department of Radiology & Nuclear Medicine, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
- 2. School of Chemistry, University of Sydney, Sydney, Australia.
- 3. Laboratory for Radiopharmaceutical Research, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.
- 4. UMR 1253, iBrain, Université de Tours, Inserm, Tours, France.
- 5. Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
- 6. Pharmidex Pharmaceutical Services Ltd., London, United Kingdom.
- 7. Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, Leuven, Belgium.
- 8. Center of Excellence on Neurodegenerative Diseases and Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy.
- 9. Department of Radiology & Nuclear Medicine, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands and BV Cyclotron VU, Amsterdam, The Netherlands.
- 10. Department of Radiology & Nuclear Medicine, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands; Laboratory for Radiopharmaceutical Research, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium and BV Cyclotron VU, Amsterdam, The Netherlands.
Description
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.
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Janssen_SciRep_2018-P9.pdf
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