Journal Article

FZJ-2021-03517

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png [18F]ALX5406: A Brain-Penetrating Prodrug for GlyT1-Specific PET Imaging

Hoffmann, C.FZJ* ; Evcüman, S.FZJ* ; Neumaier, F.FZJ* ; Zlatopolskiy, B. D. ; Humpert, S.FZJ* ; Bier, D.FZJ* ; Holschbach, M.FZJ* ; Schulze, A.FZJ* ; Endepols, H.FZJ* ; Neumaier, B. (Corresponding author)FZJ*

2021
ACS Publ. Washington, DC

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Please use a persistent id in citations: http://hdl.handle.net/2128/28655  doi:10.1021/acschemneuro.1c00284

Abstract: 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.

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Contributing Institute(s):

1. Nuklearchemie (INM-5)

Research Program(s):

1. 5253 - Neuroimaging (POF4-525) (POF4-525)

Appears in the scientific report 2021

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Database coverage:
; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Essential Science Indicators ; IF < 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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