TY  - JOUR
AU  - Dukić-Stefanović, Sladjana
AU  - Lai, Thu Hang
AU  - Toussaint, Magali
AU  - Clauß, Oliver
AU  - Jevtić, Ivana
AU  - Penjišević, Jelena
AU  - Andrić, Deana
AU  - Ludwig, Friedrich-Alexander
AU  - Gündel, Daniel
AU  - Deuther-Conrad, Winnie
AU  - Kostić Rajačić, Slađana
AU  - Brust, Peter
AU  - Teodoro, Rodrigo
PY  - 2021
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/4756
AB  - Monoamine oxidases (MAOs) play a key role in the metabolism of major monoamine neurotransmitters. In particular, the upregulation of MAO-B in Parkinson's disease, Alzheimer's disease and cancer augmented the development of selective MAO-B inhibitors for diagnostic and therapeutic purposes, such as the anti-parkinsonian MAO-B irreversible binder L-deprenyl (Selegiline®). Herein we report on the synthesis of novel fluorinated indanone derivatives for PET imaging of MAO-B in the brain. Out of our series, the derivatives 6, 8, 9 and 13 are amongst the most affine and selective ligands for MAO-B reported so far. For the derivative 6-((3-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one (6) exhibiting an outstanding affinity (Ki MAO-B = 6 nM), an automated copper-mediated radiofluorination starting from the pinacol boronic ester 17 is described. An in vitro screening in different species revealed a MAO-B region-specific accumulation of [18F]6 in rats and piglets in comparison to L-[3H]deprenyl. The pre-clinical in vivo assessment of [18F]6 in mice demonstrated the potential of indanones to readily cross the blood–brain barrier. Nonetheless, parallel in vivo metabolism studies indicated the presence of blood–brain barrier metabolites, thus arguing for further structural modifications. With the matching analytical profiles of the radiometabolite analysis from the in vitro liver microsome studies and the in vivo evaluation, the structure's elucidation of the blood–brain barrier penetrant radiometabolites is possible and will serve as basis for the development of new indanone derivatives suitable for the PET imaging of MAO-B.
PB  - Elsevier
T2  - Bioorganic and Medicinal Chemistry Letters
T1  - In vitro and in vivo evaluation of fluorinated indanone derivatives as potential positron emission tomography agents for the imaging of monoamine oxidase B in the brain
VL  - 48
SP  - 128254
DO  - 10.1016/j.bmcl.2021.128254
ER  - 

@article{
author = "Dukić-Stefanović, Sladjana and Lai, Thu Hang and Toussaint, Magali and Clauß, Oliver and Jevtić, Ivana and Penjišević, Jelena and Andrić, Deana and Ludwig, Friedrich-Alexander and Gündel, Daniel and Deuther-Conrad, Winnie and Kostić Rajačić, Slađana and Brust, Peter and Teodoro, Rodrigo",
year = "2021",
abstract = "Monoamine oxidases (MAOs) play a key role in the metabolism of major monoamine neurotransmitters. In particular, the upregulation of MAO-B in Parkinson's disease, Alzheimer's disease and cancer augmented the development of selective MAO-B inhibitors for diagnostic and therapeutic purposes, such as the anti-parkinsonian MAO-B irreversible binder L-deprenyl (Selegiline®). Herein we report on the synthesis of novel fluorinated indanone derivatives for PET imaging of MAO-B in the brain. Out of our series, the derivatives 6, 8, 9 and 13 are amongst the most affine and selective ligands for MAO-B reported so far. For the derivative 6-((3-fluorobenzyl)oxy)-2,3-dihydro-1H-inden-1-one (6) exhibiting an outstanding affinity (Ki MAO-B = 6 nM), an automated copper-mediated radiofluorination starting from the pinacol boronic ester 17 is described. An in vitro screening in different species revealed a MAO-B region-specific accumulation of [18F]6 in rats and piglets in comparison to L-[3H]deprenyl. The pre-clinical in vivo assessment of [18F]6 in mice demonstrated the potential of indanones to readily cross the blood–brain barrier. Nonetheless, parallel in vivo metabolism studies indicated the presence of blood–brain barrier metabolites, thus arguing for further structural modifications. With the matching analytical profiles of the radiometabolite analysis from the in vitro liver microsome studies and the in vivo evaluation, the structure's elucidation of the blood–brain barrier penetrant radiometabolites is possible and will serve as basis for the development of new indanone derivatives suitable for the PET imaging of MAO-B.",
publisher = "Elsevier",
journal = "Bioorganic and Medicinal Chemistry Letters",
title = "In vitro and in vivo evaluation of fluorinated indanone derivatives as potential positron emission tomography agents for the imaging of monoamine oxidase B in the brain",
volume = "48",
pages = "128254",
doi = "10.1016/j.bmcl.2021.128254"
}

Dukić-Stefanović, S., Lai, T. H., Toussaint, M., Clauß, O., Jevtić, I., Penjišević, J., Andrić, D., Ludwig, F., Gündel, D., Deuther-Conrad, W., Kostić Rajačić, S., Brust, P.,& Teodoro, R.. (2021). In vitro and in vivo evaluation of fluorinated indanone derivatives as potential positron emission tomography agents for the imaging of monoamine oxidase B in the brain. in Bioorganic and Medicinal Chemistry Letters
Elsevier., 48, 128254.
https://doi.org/10.1016/j.bmcl.2021.128254

Dukić-Stefanović S, Lai TH, Toussaint M, Clauß O, Jevtić I, Penjišević J, Andrić D, Ludwig F, Gündel D, Deuther-Conrad W, Kostić Rajačić S, Brust P, Teodoro R. In vitro and in vivo evaluation of fluorinated indanone derivatives as potential positron emission tomography agents for the imaging of monoamine oxidase B in the brain. in Bioorganic and Medicinal Chemistry Letters. 2021;48:128254.
doi:10.1016/j.bmcl.2021.128254 .

Dukić-Stefanović, Sladjana, Lai, Thu Hang, Toussaint, Magali, Clauß, Oliver, Jevtić, Ivana, Penjišević, Jelena, Andrić, Deana, Ludwig, Friedrich-Alexander, Gündel, Daniel, Deuther-Conrad, Winnie, Kostić Rajačić, Slađana, Brust, Peter, Teodoro, Rodrigo, "In vitro and in vivo evaluation of fluorinated indanone derivatives as potential positron emission tomography agents for the imaging of monoamine oxidase B in the brain" in Bioorganic and Medicinal Chemistry Letters, 48 (2021):128254,
https://doi.org/10.1016/j.bmcl.2021.128254 . .

TY  - JOUR
AU  - Jevtić, Ivana
AU  - Lai, Thu Hang
AU  - Penjišević, Jelena
AU  - Dukić-Stefanović, Sladjana
AU  - Andrić, Deana
AU  - Brust, Peter
AU  - Kostić Rajačić, Slađana
AU  - Teodoro, Rodrigo
PY  - 2020
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/4040
AB  - Herein, we report on the synthesis and pharmacological evaluation of ten novel fluorinated cinnamylpiperazines as potential monoamine oxidase B (MAO-B) ligands. The designed derivatives consist of either cinnamyl or 2-fluorocinnamyl moieties connected to 2-fluoropyridylpiperazines. The three-step synthesis starting from commercially available piperazine afforded the final products in overall yields between 9% and 29%. An in vitro competitive binding assay using l-[3H]Deprenyl as radioligand was developed and the MAO-B binding affinities of the synthesized derivatives were assessed. Docking studies revealed that the compounds 8–17 were stabilized in both MAO-B entrance and substrate cavities, thus resembling the binding pose of l-Deprenyl. Although our results revealed that the novel fluorinated cinnamylpiperazines 8–17 do not possess sufficient MAO-B binding affinity to be eligible as positron emission tomography (PET) agents, the herein developed binding assay and the insights gained within our docking studies will certainly pave the way for further development of MAO-B ligands.
PB  - MDPI
T2  - Molecules
T1  - Newly Synthesized Fluorinated Cinnamylpiperazines Possessing Low In Vitro MAO-B Binding
VL  - 25
IS  - 21
SP  - 4941
DO  - 10.3390/molecules25214941
ER  - 

@article{
author = "Jevtić, Ivana and Lai, Thu Hang and Penjišević, Jelena and Dukić-Stefanović, Sladjana and Andrić, Deana and Brust, Peter and Kostić Rajačić, Slađana and Teodoro, Rodrigo",
year = "2020",
abstract = "Herein, we report on the synthesis and pharmacological evaluation of ten novel fluorinated cinnamylpiperazines as potential monoamine oxidase B (MAO-B) ligands. The designed derivatives consist of either cinnamyl or 2-fluorocinnamyl moieties connected to 2-fluoropyridylpiperazines. The three-step synthesis starting from commercially available piperazine afforded the final products in overall yields between 9% and 29%. An in vitro competitive binding assay using l-[3H]Deprenyl as radioligand was developed and the MAO-B binding affinities of the synthesized derivatives were assessed. Docking studies revealed that the compounds 8–17 were stabilized in both MAO-B entrance and substrate cavities, thus resembling the binding pose of l-Deprenyl. Although our results revealed that the novel fluorinated cinnamylpiperazines 8–17 do not possess sufficient MAO-B binding affinity to be eligible as positron emission tomography (PET) agents, the herein developed binding assay and the insights gained within our docking studies will certainly pave the way for further development of MAO-B ligands.",
publisher = "MDPI",
journal = "Molecules",
title = "Newly Synthesized Fluorinated Cinnamylpiperazines Possessing Low In Vitro MAO-B Binding",
volume = "25",
number = "21",
pages = "4941",
doi = "10.3390/molecules25214941"
}

Jevtić, I., Lai, T. H., Penjišević, J., Dukić-Stefanović, S., Andrić, D., Brust, P., Kostić Rajačić, S.,& Teodoro, R.. (2020). Newly Synthesized Fluorinated Cinnamylpiperazines Possessing Low In Vitro MAO-B Binding. in Molecules
MDPI., 25(21), 4941.
https://doi.org/10.3390/molecules25214941

Jevtić I, Lai TH, Penjišević J, Dukić-Stefanović S, Andrić D, Brust P, Kostić Rajačić S, Teodoro R. Newly Synthesized Fluorinated Cinnamylpiperazines Possessing Low In Vitro MAO-B Binding. in Molecules. 2020;25(21):4941.
doi:10.3390/molecules25214941 .

Jevtić, Ivana, Lai, Thu Hang, Penjišević, Jelena, Dukić-Stefanović, Sladjana, Andrić, Deana, Brust, Peter, Kostić Rajačić, Slađana, Teodoro, Rodrigo, "Newly Synthesized Fluorinated Cinnamylpiperazines Possessing Low In Vitro MAO-B Binding" in Molecules, 25, no. 21 (2020):4941,
https://doi.org/10.3390/molecules25214941 . .