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
Authorized Users Only
2021
Authors
Dukić-Stefanović, SlađanaHang Lai, Thu
Toussaint, Magali
Clauß, Oliver
Jevtić, Ivana I.
Penjišević, Jelena
Andrić, Deana
Ludwig, Friedrich-Alexander
Gündel, Daniel
Deuther-Conrad, Winnie
Kostić-Rajačić, Slađana
Brust, Peter
Teodoro, Rodrigo
Article (Published version)
Metadata
Show full item recordAbstract
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. T...he 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.
Keywords:
Copper-mediated radiofluorination / Fluorine-18 / Indanone derivatives / MAO-B / PET tracersSource:
Bioorganic & Medicinal Chemistry Letters, 2021, 48, 128254-Publisher:
- Elsevier
Funding / projects:
- Structure-activity relationship of newly synthesized biological active compound (RS-MESTD-Basic Research (BR or ON)-172032)
- DAAD (grant No.57391403) within the Bilateral project “Development of new fluorinated radioligands for PET imaging of monoamine oxidase B (MAO-B)”.
Note:
- Supplementary material: https://cherry.chem.bg.ac.rs/handle/123456789/4592
Related info:
- Referenced by
https://cherry.chem.bg.ac.rs/handle/123456789/4592
DOI: 10.1016/j.bmcl.2021.128254
ISSN: 0960-894X
WoS: 000684377000020
Scopus: 2-s2.0-85110319944
URI
https://www.sciencedirect.com/science/article/pii/S0960894X21004819https://cherry.chem.bg.ac.rs/handle/123456789/4591
Collections
Institution/Community
Hemijski fakultet / Faculty of ChemistryTY - JOUR AU - Dukić-Stefanović, Slađana AU - Hang Lai, Thu AU - Toussaint, Magali AU - Clauß, Oliver AU - Jevtić, Ivana I. 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://www.sciencedirect.com/science/article/pii/S0960894X21004819 UR - https://cherry.chem.bg.ac.rs/handle/123456789/4591 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 & 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, Slađana and Hang Lai, Thu and Toussaint, Magali and Clauß, Oliver and Jevtić, Ivana I. 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 & 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., Hang Lai, T., Toussaint, M., Clauß, O., Jevtić, I. 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 & Medicinal Chemistry Letters Elsevier., 48, 128254. https://doi.org/10.1016/j.bmcl.2021.128254
Dukić-Stefanović S, Hang Lai T, Toussaint M, Clauß O, Jevtić II, 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 & Medicinal Chemistry Letters. 2021;48:128254. doi:10.1016/j.bmcl.2021.128254 .
Dukić-Stefanović, Slađana, Hang Lai, Thu, Toussaint, Magali, Clauß, Oliver, Jevtić, Ivana I., 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 & Medicinal Chemistry Letters, 48 (2021):128254, https://doi.org/10.1016/j.bmcl.2021.128254 . .