TY  - CONF
AU  - Teodoro, R.
AU  - Dukić-Stefanović, Sladjana
AU  - Lai, T. H.
AU  - Claus, O.
AU  - Jevtić, Ivana I.
AU  - Penjišević, Jelena 
AU  - Toussaint, M.
AU  - Deuther-Conrad, W.
AU  - Gundel, D.
AU  - Andrić, Deana
AU  - Scheunemann, M.
AU  - Kostić-Rajačić, Sladjana V.
AU  - Burst, P.
PY  - 2020
UR  - http://cherry.chem.bg.ac.rs/handle/123456789/5284
AB  - Ziel/Aim The monoamine oxidase B (MAO B) isoenzyme is known to be
involved in the oxidative deamination of biogenic amines. While the use of
MAO B inhibitors is already well-established for the treatment of Parkinson’s
disease, recent reports suggest its involvement in certain types of brain
tumors.1 We herein aim at the synthesis and preclinical evaluation of fluorinated indanone-based derivatives targeting MAO B in the brain via positron
emission tomography (PET).
Methodik/Methods A small series of fluorinated indanone derivatives
was obtained via the O-alkylation or esterification starting with the
commercially available 6-hydroxy-2,3-dihydro-1H-inden-1-one in one or
two steps. Binding affinities towards the human MAO isoenzymes were
estimated in vitro by radioligand displacement. HL126 was selected for
radiofluorination via its corresponding boronic acid pinacol ester. In
vitro autoradiography of [18F]HL126 was performed in mice brain slices.
In vivo evaluation of [18F]HL126 in CD-1 mice was carried out and
metabolism studies were performed in plasma and brain samples via
radio-HPLC.
Ergebnisse/Results The fluorinated indanone derivatives were synthesized
in yields ranging from 65-89 %. The fluorophenyl ether derivative, HL126,
was further selected for radiofluorination based on its high binding affinity
towards MAO B (Ki = 6.9 ± 5.3 nM). [18F]HL126 was obtained by an alcohol-enhanced copper-mediated approach via the corresponding boronic
acid pinacol ester precursor with radiochemical yields of about 11 ± 3 %,
high radiochemical purities (≥99 %) and molar activities in the range of 20
GBq/mmol. In vitro autoradiography showed a specific blockade with
selective MAO-A/B inhibitors. PET/MRI analyses revealed that [18F]HL126
readily enters the brain. Some radiometabolites do cross the blood-brain
barrier.
Schlussfolgerungen/Conclusions Although metabolism studies with [18F]
HL126 revealed the presence of radiometabolites in the brain, the high binding affinity towards MAO B and the pronounced selectivity in in vitro autoradiography studies encourage further derivatization of indanone-based
scaffolds for targeting MAO B.
C3  - 58th Annual Meeting of the German Society for Nuclear Medicine,  Leipzig, Germany
T1  - Development of fluorinated indanone-based derivatives for the imaging of monoamine oxidase B via positron emission tomography
VL  - 59
DO  - 10.1055/s-0040-1708201
ER  - 

@conference{
author = "Teodoro, R. and Dukić-Stefanović, Sladjana and Lai, T. H. and Claus, O. and Jevtić, Ivana I. and Penjišević, Jelena  and Toussaint, M. and Deuther-Conrad, W. and Gundel, D. and Andrić, Deana and Scheunemann, M. and Kostić-Rajačić, Sladjana V. and Burst, P.",
year = "2020",
abstract = "Ziel/Aim The monoamine oxidase B (MAO B) isoenzyme is known to be
involved in the oxidative deamination of biogenic amines. While the use of
MAO B inhibitors is already well-established for the treatment of Parkinson’s
disease, recent reports suggest its involvement in certain types of brain
tumors.1 We herein aim at the synthesis and preclinical evaluation of fluorinated indanone-based derivatives targeting MAO B in the brain via positron
emission tomography (PET).
Methodik/Methods A small series of fluorinated indanone derivatives
was obtained via the O-alkylation or esterification starting with the
commercially available 6-hydroxy-2,3-dihydro-1H-inden-1-one in one or
two steps. Binding affinities towards the human MAO isoenzymes were
estimated in vitro by radioligand displacement. HL126 was selected for
radiofluorination via its corresponding boronic acid pinacol ester. In
vitro autoradiography of [18F]HL126 was performed in mice brain slices.
In vivo evaluation of [18F]HL126 in CD-1 mice was carried out and
metabolism studies were performed in plasma and brain samples via
radio-HPLC.
Ergebnisse/Results The fluorinated indanone derivatives were synthesized
in yields ranging from 65-89 %. The fluorophenyl ether derivative, HL126,
was further selected for radiofluorination based on its high binding affinity
towards MAO B (Ki = 6.9 ± 5.3 nM). [18F]HL126 was obtained by an alcohol-enhanced copper-mediated approach via the corresponding boronic
acid pinacol ester precursor with radiochemical yields of about 11 ± 3 %,
high radiochemical purities (≥99 %) and molar activities in the range of 20
GBq/mmol. In vitro autoradiography showed a specific blockade with
selective MAO-A/B inhibitors. PET/MRI analyses revealed that [18F]HL126
readily enters the brain. Some radiometabolites do cross the blood-brain
barrier.
Schlussfolgerungen/Conclusions Although metabolism studies with [18F]
HL126 revealed the presence of radiometabolites in the brain, the high binding affinity towards MAO B and the pronounced selectivity in in vitro autoradiography studies encourage further derivatization of indanone-based
scaffolds for targeting MAO B.",
journal = "58th Annual Meeting of the German Society for Nuclear Medicine,  Leipzig, Germany",
title = "Development of fluorinated indanone-based derivatives for the imaging of monoamine oxidase B via positron emission tomography",
volume = "59",
doi = "10.1055/s-0040-1708201"
}

Teodoro, R., Dukić-Stefanović, S., Lai, T. H., Claus, O., Jevtić, I. I., Penjišević, J., Toussaint, M., Deuther-Conrad, W., Gundel, D., Andrić, D., Scheunemann, M., Kostić-Rajačić, S. V.,& Burst, P.. (2020). Development of fluorinated indanone-based derivatives for the imaging of monoamine oxidase B via positron emission tomography. in 58th Annual Meeting of the German Society for Nuclear Medicine,  Leipzig, Germany, 59.
https://doi.org/10.1055/s-0040-1708201

Teodoro R, Dukić-Stefanović S, Lai TH, Claus O, Jevtić II, Penjišević J, Toussaint M, Deuther-Conrad W, Gundel D, Andrić D, Scheunemann M, Kostić-Rajačić SV, Burst P. Development of fluorinated indanone-based derivatives for the imaging of monoamine oxidase B via positron emission tomography. in 58th Annual Meeting of the German Society for Nuclear Medicine,  Leipzig, Germany. 2020;59.
doi:10.1055/s-0040-1708201 .

Teodoro, R., Dukić-Stefanović, Sladjana, Lai, T. H., Claus, O., Jevtić, Ivana I., Penjišević, Jelena , Toussaint, M., Deuther-Conrad, W., Gundel, D., Andrić, Deana, Scheunemann, M., Kostić-Rajačić, Sladjana V., Burst, P., "Development of fluorinated indanone-based derivatives for the imaging of monoamine oxidase B via positron emission tomography" in 58th Annual Meeting of the German Society for Nuclear Medicine,  Leipzig, Germany, 59 (2020),
https://doi.org/10.1055/s-0040-1708201 . .

TY  - CONF
AU  - Penjišević, Jelena 
AU  - Andrić, Deana
AU  - Dukić-Stefanović, Sladjana
AU  - Spalholz, T.
AU  - Burst, P.
AU  - Kostić-Rajačić, Sladjana V.
PY  - 2019
UR  - http://cherry.chem.bg.ac.rs/handle/123456789/5283
AB  - Serotonin 5HT1a receptor belongs to a class of G-protein coupled receptors. It serves as a
potential target for neurological disorders such as depression, anxiety etc. It is a well-known
fact that N-arylpiperazine moiety is present in compounds with pronounced 5HT1a activity.
Taking into account previously published results1
novel structures of N-{4-[2-(4-
arylpiperazin-1-yl)ethyl]phenyl}arylamides (Figure 1.) were designed for target synthesis.
Proposed modifications include: different position of hydroxyl group in aryl amide part of
molecule and addition of methoxy and chloro substituents to the phenyl ring of parent
compounds, since their introduction in the molecule leads to increased receptor affinity.
New compounds were synthesized by acylation of N-arylpiperazines using 4-
nitrophenylacetic acid. Obtained amides were converted in 1-(4-nitrophenethyl)-4-
arylpiperazines using diborane in THF. Reduction of nitro compounds by Ra/Ni provided 1-
(4-aminophenethyl)-4-arylpiperazines. Target arylamides were obtained by condensation 1-
(4-aminophenethyl)-4-arylpiperazines with corresponding aryl acids in presence of
propylphosphoric acid anhydride (PPAA) in DMF.
All newly synthesized compounds were evaluated for their activity toward 5HT1a receptors
by in vitro competitive displacement assay of [3H] 8-OH-DPAT. HEK cell line were used as a
source of 5HT1a receptors.
Introduction of 2-methoxy and 2,3-dichloro groups,as well as meta and para hydroxyl group
in molecule resulted in increment of affinity toward 5HT1a receptors comparing to the parent
compounds.
C3  - 11th Joint Meeting on Medicinal Chemistry 2019, Prague, Czech Republic, 2019.
T1  - Synthesis and pharmacological evaluation of N-{4-[2-(4-arylpiperazin-1-yl) ethyl] phenyl}arylamides
UR  - https://hdl.handle.net/21.15107/rcub_cherry_5283
ER  - 

@conference{
author = "Penjišević, Jelena  and Andrić, Deana and Dukić-Stefanović, Sladjana and Spalholz, T. and Burst, P. and Kostić-Rajačić, Sladjana V.",
year = "2019",
abstract = "Serotonin 5HT1a receptor belongs to a class of G-protein coupled receptors. It serves as a
potential target for neurological disorders such as depression, anxiety etc. It is a well-known
fact that N-arylpiperazine moiety is present in compounds with pronounced 5HT1a activity.
Taking into account previously published results1
novel structures of N-{4-[2-(4-
arylpiperazin-1-yl)ethyl]phenyl}arylamides (Figure 1.) were designed for target synthesis.
Proposed modifications include: different position of hydroxyl group in aryl amide part of
molecule and addition of methoxy and chloro substituents to the phenyl ring of parent
compounds, since their introduction in the molecule leads to increased receptor affinity.
New compounds were synthesized by acylation of N-arylpiperazines using 4-
nitrophenylacetic acid. Obtained amides were converted in 1-(4-nitrophenethyl)-4-
arylpiperazines using diborane in THF. Reduction of nitro compounds by Ra/Ni provided 1-
(4-aminophenethyl)-4-arylpiperazines. Target arylamides were obtained by condensation 1-
(4-aminophenethyl)-4-arylpiperazines with corresponding aryl acids in presence of
propylphosphoric acid anhydride (PPAA) in DMF.
All newly synthesized compounds were evaluated for their activity toward 5HT1a receptors
by in vitro competitive displacement assay of [3H] 8-OH-DPAT. HEK cell line were used as a
source of 5HT1a receptors.
Introduction of 2-methoxy and 2,3-dichloro groups,as well as meta and para hydroxyl group
in molecule resulted in increment of affinity toward 5HT1a receptors comparing to the parent
compounds.",
journal = "11th Joint Meeting on Medicinal Chemistry 2019, Prague, Czech Republic, 2019.",
title = "Synthesis and pharmacological evaluation of N-{4-[2-(4-arylpiperazin-1-yl) ethyl] phenyl}arylamides",
url = "https://hdl.handle.net/21.15107/rcub_cherry_5283"
}

Penjišević, J., Andrić, D., Dukić-Stefanović, S., Spalholz, T., Burst, P.,& Kostić-Rajačić, S. V.. (2019). Synthesis and pharmacological evaluation of N-{4-[2-(4-arylpiperazin-1-yl) ethyl] phenyl}arylamides. in 11th Joint Meeting on Medicinal Chemistry 2019, Prague, Czech Republic, 2019..
https://hdl.handle.net/21.15107/rcub_cherry_5283

Penjišević J, Andrić D, Dukić-Stefanović S, Spalholz T, Burst P, Kostić-Rajačić SV. Synthesis and pharmacological evaluation of N-{4-[2-(4-arylpiperazin-1-yl) ethyl] phenyl}arylamides. in 11th Joint Meeting on Medicinal Chemistry 2019, Prague, Czech Republic, 2019.. 2019;.
https://hdl.handle.net/21.15107/rcub_cherry_5283 .

Penjišević, Jelena , Andrić, Deana, Dukić-Stefanović, Sladjana, Spalholz, T., Burst, P., Kostić-Rajačić, Sladjana V., "Synthesis and pharmacological evaluation of N-{4-[2-(4-arylpiperazin-1-yl) ethyl] phenyl}arylamides" in 11th Joint Meeting on Medicinal Chemistry 2019, Prague, Czech Republic, 2019. (2019),
https://hdl.handle.net/21.15107/rcub_cherry_5283 .