A 18F-Labeled Fluorobutyl-Substituted Spirocyclic Piperidine Derivative as a Selective Radioligand for PET Imaging of Sigma1 Receptors

✍ Scribed by Dr. Aurélie Maisonial; Dr. Eva Große Maestrup; Dr. Steffen Fischer; Dr. Achim Hiller; Dr. Matthias Scheunemann; Dr. Christian Wiese; Dr. Dirk Schepmann; Prof. Jörg Steinbach; Dr. Winnie Deuther-Conrad; Prof. Bernhard Wünsch; Prof. Peter Brust

• Publisher: John Wiley and Sons
• Year: 2011
• Tongue: English
• Weight: 491 KB
• Volume: 6
• Category: Article
• ISSN: 1860-7179
• DOI: 10.1002/cmdc.201100108

✦ Synopsis

Abstract

In this study, we synthesized and evaluated a new spirocyclic piperidine derivative 3, containing a 4‐fluorobutyl side chain, as a PET radioligand for neuroimaging of σ~1~ receptors. In vitro, compound 3 displayed high affinity for σ~1~ receptors (K~i~=1.2 nM) as well as high selectivity. [^18^F]3 radiosynthesis was performed from the corresponding tosylate precursor, with high radiochemical yield (45–51 %), purity (>98 %), and specific activity (>201 GBq μmol^−1^). Metabolic stability of [^18^F]3 in the brain of CD‐1 mice was verified, and no penetration of peripheral radiometabolites into the cerebral tissue was observed. Results of ex vivo autoradiography revealed that the distribution of [^18^F]3 in the brain corresponded to regions with high σ~1~ receptor density. The highest region‐specific total‐to‐nonspecific ratio was determined in the facial nucleus (4.00). Biodistribution studies indicated rapid and high levels in brain uptake of [^18^F]3 (2.2 % ID per gram at 5 min p.i.). Pre‐administration of haloperidol significantly inhibited [^18^F]3 uptake into the brain and σ~1~ receptor‐expressing organs, further confirming in vivo target specificity.