This title appears in the Scientific Report :
2021
Please use the identifier:
http://hdl.handle.net/2128/28655 in citations.
Please use the identifier: http://dx.doi.org/10.1021/acschemneuro.1c00284 in citations.
[18F]ALX5406: A Brain-Penetrating Prodrug for GlyT1-Specific PET Imaging
[18F]ALX5406: A Brain-Penetrating Prodrug for GlyT1-Specific PET Imaging
Selective inhibition of glycine transporter 1 (GlyT1) has emerged as a potential approach to alleviate N-methyl-D-aspartate receptor (NMDAR) hypofunction in patients with schizophrenia and cognitive decline. ALX5407 is a potent and selective inhibitor of GlyT1 derived from the metabolic intermediate...
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Personal Name(s): | Hoffmann, Chris |
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Evcüman, Sibel / Neumaier, Felix / Zlatopolskiy, Boris D. / Humpert, Swen / Bier, Dirk / Holschbach, Marcus / Schulze, Annette / Endepols, Heike / Neumaier, Bernd (Corresponding author) | |
Contributing Institute: |
Nuklearchemie; INM-5 |
Published in: | ACS chemical neuroscience, 12 (2021) 18, S. 3335 - 3346 |
Imprint: |
Washington, DC
ACS Publ.
2021
|
DOI: |
10.1021/acschemneuro.1c00284 |
Document Type: |
Journal Article |
Research Program: |
Neuroimaging |
Link: |
Published on 2021-08-27. Available in OpenAccess from 2022-08-27. Published on 2021-08-27. Available in OpenAccess from 2022-08-27. Restricted |
Publikationsportal JuSER |
Please use the identifier: http://dx.doi.org/10.1021/acschemneuro.1c00284 in citations.
Selective inhibition of glycine transporter 1 (GlyT1) has emerged as a potential approach to alleviate N-methyl-D-aspartate receptor (NMDAR) hypofunction in patients with schizophrenia and cognitive decline. ALX5407 is a potent and selective inhibitor of GlyT1 derived from the metabolic intermediate sarcosine (N-methylglycine) that showed antipsychotic potential in a number of animal models. Whereas clinical application of ALX5407 is limited by adverse effects on motor performance and respiratoryfunction, a suitably radiolabeled drug could represent a promising PET tracer for the visualization of GlyT1 in the brain. Herein, [18F]ALX5407 and the corresponding methyl ester, [18F]ALX5406, were prepared by alcoholenhanced copper mediated radiofluorination and studied in vitro in rat brain slices and in vivo in normal rats. [18F]ALX5407 demonstrated accumulation consistent with the distribution of GlyT1 in in vitro autoradiographic studies but no brain uptake in μPET experiments in naıv̈ e rats. In contrast, the methyl ester [18F]ALX5406 rapidly entered the brain and was enzymatically transformed into [18F]ALX5407, resulting in a regional accumulation pattern consistent with GlyT1 specific binding. We conclude that [18F]ALX5406 is a promising and easily accessible PET probe for preclinical in vivo imaging of GlyT1 in the brain. |