Hoffmann, Chris ORCID: 0000-0003-1093-0183, Evcueman, Sibel, Neumaier, Felix ORCID: 0000-0002-6376-6391, Zlatopolskiy, Boris D., Humpert, Swen ORCID: 0000-0002-1995-0714, Bier, Dirk, Holschbach, Marcus, Schulze, Annette, Endepols, Heike and Neumaier, Bernd ORCID: 0000-0001-5425-3116 (2021). [F-18]ALX5406: A Brain-Penetrating Prodrug for GlyT1-Specific PET Imaging. ACS Chem. Neurosci., 12 (18). S. 3335 - 3347. WASHINGTON: AMER CHEMICAL SOC. ISSN 1948-7193

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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 respiratory function, a suitably radiolabeled drug could represent a promising PET tracer for the visualization of GlyT1 in the brain. Herein, [F-18]ALX5407 and the corresponding methyl ester, [F-18]ALX5406, were prepared by alcoholenhanced copper mediated radiofluorination and studied in vitro in rat brain slices and in vivo in normal rats. [F-18]ALX5407 demonstrated accumulation consistent with the distribution of GlyT1 in in vitro autoradiographic studies but no brain uptake in mu PET experiments in naive rats. In contrast, the methyl ester [F-18]ALX5406 rapidly entered the brain and was enzymatically transformed into [F-18]ALX5407, resulting in a regional accumulation pattern consistent with GlyT1 specific binding. We conclude that [F-18]ALX5406 is a promising and easily accessible PET probe for preclinical in vivo imaging of GlyT1 in the brain.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Hoffmann, ChrisUNSPECIFIEDorcid.org/0000-0003-1093-0183UNSPECIFIED
Evcueman, SibelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neumaier, FelixUNSPECIFIEDorcid.org/0000-0002-6376-6391UNSPECIFIED
Zlatopolskiy, Boris D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Humpert, SwenUNSPECIFIEDorcid.org/0000-0002-1995-0714UNSPECIFIED
Bier, DirkUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Holschbach, MarcusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schulze, AnnetteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Endepols, HeikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neumaier, BerndUNSPECIFIEDorcid.org/0000-0001-5425-3116UNSPECIFIED
URN: urn:nbn:de:hbz:38-582082
DOI: 10.1021/acschemneuro.1c00284
Journal or Publication Title: ACS Chem. Neurosci.
Volume: 12
Number: 18
Page Range: S. 3335 - 3347
Date: 2021
Publisher: AMER CHEMICAL SOC
Place of Publication: WASHINGTON
ISSN: 1948-7193
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
TRANSPORTER TYPE-1 INHIBITOR; CENTRAL-NERVOUS-SYSTEM; HIGH-DOSE GLYCINE; NEGATIVE SYMPTOMS; MEDIATED RESPONSES; N-METHYLGLYCINE; 5-HT2C RECEPTOR; DOUBLE-BLIND; D-SERINE; IN-VIVOMultiple languages
Biochemistry & Molecular Biology; Chemistry, Medicinal; NeurosciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/58208

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