Development of fluorinated indanone-based derivatives for the imaging of monoamine oxidase B via positron emission tomography
Аутори
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.
Конференцијски прилог (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт
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.
Извор:
58th Annual Meeting of the German Society for Nuclear Medicine, Leipzig, Germany, 2020, 59Финансирање / пројекти:
- Проучавање односа структуре и активности новосинтетисаних биолошки активних супстанци (RS-MESTD-Basic Research (BR or ON)-172032)
Колекције
Институција/група
Hemijski fakultet / Faculty of ChemistryTY - 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 . .