At first the role of σ1 receptors in various neurological, psychiatric and neurodegenerative disorders is discussed. In the second part, the principle of positron emission tomography (PET ) is described and the known fluorinated PET tracers for labeling of σ1 receptors are presented. The third part focuses on fluoroalkyl substituted spirocyclic PET tracers, which represent the most promising class of fluorinated PET tracers reported so far. The homologous fluoroalkyl derivatives 12-15 show high σ1 affinity (K i = 0.59-1.4 nM) and high selectivity over the σ2 subtype (408-1331-fold). The enantiomers of the fluoroethyl derivative fluspidine 13 were prepared and pharmacologically characterized. Whereas the (S)-configured enantiomer (S)-13 (K i = 2.3 nM) is 4-fold less active than the (R)-enantiomer (R)-13 (K i = 0.57 nM), (S)-13 is metabolically more stable. The interactions of (S)-13 and (R)-13 with the σ1 receptor were analyzed at the molecular level using the 3D homology model. In an automated radiosynthesis [18F](S)-13 and [18F](R)-13 were prepared by nucleophilic substitution of the tosylates (S)-17 and (R)-17 with K[18F]F in high radiochemical yield, high radiochemical purity and short reaction time. Application of both enantiomers [18F](S)-13 and [18F](R)-13 to mice and piglets led to fast uptake into the brain, but [18F](R)-13 did not show washout from the brain indicating a quasi-irreversible binding. Both radiotracers [18F](S)-13 and [18F](R)-13 were able to label regions in the mouse and piglet brain with high σ1 receptor density. The specific binding of the enantiomeric tracers [18F](S)-13 and [18F](R)-13 could be replaced by the selective σ1 ligand SA4503.

Fluorinated PET Tracers for Molecular Imaging of σ1 Receptors in the Central Nervous System.

LAURINI, ERIK;PRICL, SABRINA;
2017

Abstract

At first the role of σ1 receptors in various neurological, psychiatric and neurodegenerative disorders is discussed. In the second part, the principle of positron emission tomography (PET ) is described and the known fluorinated PET tracers for labeling of σ1 receptors are presented. The third part focuses on fluoroalkyl substituted spirocyclic PET tracers, which represent the most promising class of fluorinated PET tracers reported so far. The homologous fluoroalkyl derivatives 12-15 show high σ1 affinity (K i = 0.59-1.4 nM) and high selectivity over the σ2 subtype (408-1331-fold). The enantiomers of the fluoroethyl derivative fluspidine 13 were prepared and pharmacologically characterized. Whereas the (S)-configured enantiomer (S)-13 (K i = 2.3 nM) is 4-fold less active than the (R)-enantiomer (R)-13 (K i = 0.57 nM), (S)-13 is metabolically more stable. The interactions of (S)-13 and (R)-13 with the σ1 receptor were analyzed at the molecular level using the 3D homology model. In an automated radiosynthesis [18F](S)-13 and [18F](R)-13 were prepared by nucleophilic substitution of the tosylates (S)-17 and (R)-17 with K[18F]F in high radiochemical yield, high radiochemical purity and short reaction time. Application of both enantiomers [18F](S)-13 and [18F](R)-13 to mice and piglets led to fast uptake into the brain, but [18F](R)-13 did not show washout from the brain indicating a quasi-irreversible binding. Both radiotracers [18F](S)-13 and [18F](R)-13 were able to label regions in the mouse and piglet brain with high σ1 receptor density. The specific binding of the enantiomeric tracers [18F](S)-13 and [18F](R)-13 could be replaced by the selective σ1 ligand SA4503.
File in questo prodotto:
File Dimensione Formato  
237-SpringerBuch.pdf

non disponibili

Tipologia: Documento in Pre-print
Licenza: Digital Rights Management non definito
Dimensione 1.89 MB
Formato Adobe PDF
1.89 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
cover+pdf p.31-38.pdf

non disponibili

Tipologia: Documento in Versione Editoriale
Licenza: Digital Rights Management non definito
Dimensione 965.66 kB
Formato Adobe PDF
965.66 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11368/2897746
Citazioni
  • ???jsp.display-item.citation.pmc??? 4
  • Scopus 9
  • ???jsp.display-item.citation.isi??? 9
social impact