In vitro phosphodiesterase 10A (PDE10A) binding in whole hemisphere human brain using the PET radioligand [18F]MNI-659

Highly specific and sensitive biomarkers for pathologies related to dysfunctions in the basal ganglia circuit are of great value to assess therapeutic efficacy not only clinically to establish an early diagnosis, but also in terms of monitoring the efficacy of therapeutic interventions and decelerat...

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Main Authors: Svedberg, Marie M., Varnäs, Katarina, Varrone, Andrea, Mitsios, Nicholas, Mulder, Jan, Gulyás, Balázs, Beaumont, Vahri, Munoz-Sanjuan, Ignacio, Zaleska, Margaret M., Schmidt, Christopher J., Halldin, Christer, Mrzljak, Ladislav
Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
Format: Article
Language:English
Published: 2021
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Online Access:https://hdl.handle.net/10356/151071
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spelling sg-ntu-dr.10356-1510712021-06-03T00:38:39Z In vitro phosphodiesterase 10A (PDE10A) binding in whole hemisphere human brain using the PET radioligand [18F]MNI-659 Svedberg, Marie M. Varnäs, Katarina Varrone, Andrea Mitsios, Nicholas Mulder, Jan Gulyás, Balázs Beaumont, Vahri Munoz-Sanjuan, Ignacio Zaleska, Margaret M. Schmidt, Christopher J. Halldin, Christer Mrzljak, Ladislav Lee Kong Chian School of Medicine (LKCMedicine) Science::Medicine Autoradiography Phosphodiesterase 10A Highly specific and sensitive biomarkers for pathologies related to dysfunctions in the basal ganglia circuit are of great value to assess therapeutic efficacy not only clinically to establish an early diagnosis, but also in terms of monitoring the efficacy of therapeutic interventions and decelerated neurodegeneration. The phosphodiesterase 10A (PDE10A) enzyme plays a central role in striatal signaling and is implicated in several neuropsychiatric disorders involving striatal pathology, such as Huntingtońs disease (HD) and schizophrenia. Inhibition of PDE10A activates the neurons in the striatum and consequently leads to alteration of behavioral aspects modulated by the striatal circuit. [18F]MNI-659, (2-(2-(3-(4-(2-[18F]fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione), is a newly developed PET radioligand that shows a high binding to PDE10A in the human brain in vivo. In the present study, we examined the in vitro binding of [18F]MNI-659 in human postmortem brain to gain a better understanding of the presence, density, disease-related alterations and therapy related to changes in PDE10A expression. The results show high specific binding of [18F]MNI-659 in the caudate nucleus, putamen and the hippocampal formation. Low specific [18F]MNI-659 binding was detected in nucleus accumbens in comparison to the caudate nucleus and putamen. In vitro binding studies with [18F]MNI-659 will facilitate in elucidating better understanding of the role of PDE10A activity in health and disease that may lead to new diagnostic opportunities in HD. This work was supported by the CHDI Foundation. The authors thank the members of the PET group at the Karolinska Institutet for excellent assistance; in particular Siv Eriksson for assistance with the autoradiography studies. We also thank Molecular Neuroimaging L.L.C. (MNI) for providing the [18F]MNI-659 precursor. 2021-06-03T00:38:39Z 2021-06-03T00:38:39Z 2019 Journal Article Svedberg, M. M., Varnäs, K., Varrone, A., Mitsios, N., Mulder, J., Gulyás, B., Beaumont, V., Munoz-Sanjuan, I., Zaleska, M. M., Schmidt, C. J., Halldin, C. & Mrzljak, L. (2019). In vitro phosphodiesterase 10A (PDE10A) binding in whole hemisphere human brain using the PET radioligand [18F]MNI-659. Brain Research, 1711, 140-145. https://dx.doi.org/10.1016/j.brainres.2019.01.021 0006-8993 https://hdl.handle.net/10356/151071 10.1016/j.brainres.2019.01.021 30664847 2-s2.0-85060753971 1711 140 145 en Brain Research © 2019 Elsevier B.V. All rights reserved.
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Science::Medicine
Autoradiography
Phosphodiesterase 10A
spellingShingle Science::Medicine
Autoradiography
Phosphodiesterase 10A
Svedberg, Marie M.
Varnäs, Katarina
Varrone, Andrea
Mitsios, Nicholas
Mulder, Jan
Gulyás, Balázs
Beaumont, Vahri
Munoz-Sanjuan, Ignacio
Zaleska, Margaret M.
Schmidt, Christopher J.
Halldin, Christer
Mrzljak, Ladislav
In vitro phosphodiesterase 10A (PDE10A) binding in whole hemisphere human brain using the PET radioligand [18F]MNI-659
description Highly specific and sensitive biomarkers for pathologies related to dysfunctions in the basal ganglia circuit are of great value to assess therapeutic efficacy not only clinically to establish an early diagnosis, but also in terms of monitoring the efficacy of therapeutic interventions and decelerated neurodegeneration. The phosphodiesterase 10A (PDE10A) enzyme plays a central role in striatal signaling and is implicated in several neuropsychiatric disorders involving striatal pathology, such as Huntingtońs disease (HD) and schizophrenia. Inhibition of PDE10A activates the neurons in the striatum and consequently leads to alteration of behavioral aspects modulated by the striatal circuit. [18F]MNI-659, (2-(2-(3-(4-(2-[18F]fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione), is a newly developed PET radioligand that shows a high binding to PDE10A in the human brain in vivo. In the present study, we examined the in vitro binding of [18F]MNI-659 in human postmortem brain to gain a better understanding of the presence, density, disease-related alterations and therapy related to changes in PDE10A expression. The results show high specific binding of [18F]MNI-659 in the caudate nucleus, putamen and the hippocampal formation. Low specific [18F]MNI-659 binding was detected in nucleus accumbens in comparison to the caudate nucleus and putamen. In vitro binding studies with [18F]MNI-659 will facilitate in elucidating better understanding of the role of PDE10A activity in health and disease that may lead to new diagnostic opportunities in HD.
author2 Lee Kong Chian School of Medicine (LKCMedicine)
author_facet Lee Kong Chian School of Medicine (LKCMedicine)
Svedberg, Marie M.
Varnäs, Katarina
Varrone, Andrea
Mitsios, Nicholas
Mulder, Jan
Gulyás, Balázs
Beaumont, Vahri
Munoz-Sanjuan, Ignacio
Zaleska, Margaret M.
Schmidt, Christopher J.
Halldin, Christer
Mrzljak, Ladislav
format Article
author Svedberg, Marie M.
Varnäs, Katarina
Varrone, Andrea
Mitsios, Nicholas
Mulder, Jan
Gulyás, Balázs
Beaumont, Vahri
Munoz-Sanjuan, Ignacio
Zaleska, Margaret M.
Schmidt, Christopher J.
Halldin, Christer
Mrzljak, Ladislav
author_sort Svedberg, Marie M.
title In vitro phosphodiesterase 10A (PDE10A) binding in whole hemisphere human brain using the PET radioligand [18F]MNI-659
title_short In vitro phosphodiesterase 10A (PDE10A) binding in whole hemisphere human brain using the PET radioligand [18F]MNI-659
title_full In vitro phosphodiesterase 10A (PDE10A) binding in whole hemisphere human brain using the PET radioligand [18F]MNI-659
title_fullStr In vitro phosphodiesterase 10A (PDE10A) binding in whole hemisphere human brain using the PET radioligand [18F]MNI-659
title_full_unstemmed In vitro phosphodiesterase 10A (PDE10A) binding in whole hemisphere human brain using the PET radioligand [18F]MNI-659
title_sort in vitro phosphodiesterase 10a (pde10a) binding in whole hemisphere human brain using the pet radioligand [18f]mni-659
publishDate 2021
url https://hdl.handle.net/10356/151071
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