Development of highly potent phosphodiesterase 10A (PDE10A) inhibitors: Synthesis and in vitro evaluation of 1,8-dipyridinyl- and 1-pyridinyl-substituted imidazo[1,5-a ]quinoxalines

Article abstract of DOI:10.1016/j.ejmech.2015.10.028

Herein we report the synthesis of fluorinated inhibitors of phosphodiesterase 10A (PDE10A) which can be used potentially as lead structure for the development of a ¹⁸F-labeled PDE10A imaging agent for positron emission tomography. The use of or

Full text of DOI:10.1016/j.ejmech.2015.10.028

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Development of highly potent phosphodiesterase 10A (PDE10A) inhibitors:
Synthesis and in vitro evaluation of 1,8-dipyridinyl- and 1-pyridinyl-substituted
imidazo[1,5-a]quinoxalines
Sally Wagner, Matthias Scheunemann, Karolin Dipper, Ute Egerland, Norbert
Hoefgen, Jörg Steinbach, Peter Brust
PII:
S0223-5234(15)30310-X
10.1016/j.ejmech.2015.10.028
EJMECH 8163
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 22 May 2015
Revised Date: 13 October 2015
Accepted Date: 14 October 2015
Please cite this article as: S. Wagner, M. Scheunemann, K. Dipper, U. Egerland, N. Hoefgen,
J. Steinbach, P. Brust, Development of highly potent phosphodiesterase 10A (PDE10A)
inhibitors: Synthesis and in vitro evaluation of 1,8-dipyridinyl- and 1-pyridinyl-substituted
imidazo[1,5-a]quinoxalines, European Journal of Medicinal Chemistry (2015), doi: 10.1016/
j.ejmech.2015.10.028.
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Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
ACCEPTED MANUSCRIPT
Development of highly potent phosphodiesterase 10A (PDE10A)
inhibitors: Synthesis and in vitro evaluation of 1,8-dipyridinyl- and 1-
pyridinyl-substituted imidazo[1,5-a]quinoxalines
Sally Wagnera, , Matthias Scheunemanna, Karolin Dippera, Ute Egerlandb, Norbert Hoefgenb,
Jörg Steinbacha and Peter Brusta
aHelmholtz-Zentrum Dresden - Rossendorf, Institute of Radiopharmaceutical Cancer Research, Research
Site Leipzig, Dept. of Neuroradiopharmaceuticals, Permoserstrasse 15, 04318 Leipzig, Germany
bBioCrea GmbH, Meissner Strasse 191, 01445 Radebeul, Germany
e-mail:
Sally Wagner s.wagner@hzdr.de
Matthias Scheunemann
Karolin Dipper
Ute Egerland
m.scheunemann@hzdr.de
karolin.dipper@googlemail.com
ute.egerland@outlook.de
Norbert.Hoefgen@t-online.de
j.steinbach@hzdr.de
Norbert Hoefgen
Jörg Steinbach
Peter Brust
p.brust@hzdr.de
Corresponding author. Tel.: +49-341-2341794635; e-mail: s.wagner@hzdr.de (S.Wagner)

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
ACCEPTED MANUSCRIPT
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Development of highly potent phosphodiesterase 10A (PDE10A) inhibitors:
Synthesis and in vitro evaluation of 1,8-dipyridinyl- and 1-pyridinyl-
substituted imidazo[1,5-a]quinoxalines
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Sally Wagnera, , Matthias Scheunemanna, Karolin Dippera, Ute Egerlandb, Norbert Hoefgenb, Jörg
Steinbacha and Peter Brusta
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aHelmholtz-Zentrum Dresden - Rossendorf, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Dept. of
Neuroradiopharmaceuticals, Permoserstrasse 15, 04318 Leipzig, Germany
bBioCrea GmbH, Meissner Strasse 191, 01445 Radebeul, Germany
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Abstract: Herein we report the synthesis of fluorinated inhibitors of phosphodiesterase 10A (PDE10A)
which can be used potentially as lead structure for the development of a F-18 labeled PDE10A imaging
agent for positron emission tomography. The use of ortho-fluoropyridines as residues could potentially
enable the introduction of F-18 through nucleophillic substitution for radiolabeling purposes. 2-
Fluoropyridines are introduced by a Suzuki coupling at different positions of the molecule. The reference
compounds, 1,8-dipyridinylimidazo[1,5-a]quinoxalines and 1-pyridinylimidazo[1,5-a]quinoxalines, show
inhibitory potencies at best in the subnanomolar range and selectivity factors greater than 38 against other
PDE’s. 1,8-Dipyridinylimidazo[1,5-a]quinoxalines are more potent inhibitors than 1-pyridinylimidazo[1,5-
a]quinoxalines. Using 2-fluoro-3-pyridinyl as residue provided the most potent inhibitors 16 (IC50
0.12 nM), 17 (IC50 = 0.048 nM) and 32 (IC50 = 0.037 nM).
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Keywords: PDE10A inhibitor, Imidazo[1,5-a]quinoxalines, PDE10A imaging agent.
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1. Introduction
Phosphodiesterases (PDEs) represent a superfamily of enzymes capable of inactivating the second
messengers cAMP or/and cGMP. These signaling molecules generated by cyclases regulate a wide range
of physiological processes. By controlling cAMP/cGMP levels PDEs are key regulators of cellular signal
transduction. So far 11 subfamilies of phosphodiesterases are known differing in structure, substrate
specificity and inhibitor sensitivity. Classification by substrate specificity divides PDEs into cAMP-specific,
cGMP-specific and dual substrate enzymes.
PDE10A is a dual substrate enzyme discovered in 1999 [1-4]. It is the only member of the PDE10
family. Across mammalian species PDE10A is primarily expressed in the striatum [5, 6], the main recipient
of dopaminergic afferents from the substantia nigra [7]. Due to its high striatal expression PDE10A
inhibitors are regarded as therapeutic approach in the treatment of diseases related to striatal dysfunction
such as schizophrenia [8]. The antipsychotic-like effect of PDE10A inhibitors has been proven in animal
models [9-11]. PDE10A inhibitors represent a new therapeutic treatment of negative, positive and
cognitive symptoms of schizophrenia with a lower risk for side effects than traditional antipsychotics.
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Corresponding author. Tel.: +49-341-2341794635; e-mail: s.wagner@hzdr.de (S.Wagner)