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

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 σ₁ receptors. In vitro, compound 3 displayed high affinity for σ₁ receptors (K(i) =1.2 nM) as well as high selectivity. [¹⁸F]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 [¹⁸F]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 [¹⁸F]3 in the brain corresponded to regions with high σ₁ 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 [¹⁸F]3 (2.2 % ID per gram at 5 min p.i.). Pre-administration of haloperidol significantly inhibited [¹⁸F]3 uptake into the brain and σ₁ receptor-expressing organs, further confirming in vivo target specificity.

Pharmacophore Models and Development of Spirocyclic Ligands for σ1 Receptors

“…Due to its high 1 affinity and selectivity over more than 60 further targets including the 2 subtype and the hERG channel [37], the spiro[[2]benzofuran-1,4'-piperidine] 3 served as starting point for the development of fluorinated PET-tracers for neuroimaging of 1 receptors in the CNS. [ 18 F]-Fluorine was introduced into an alkyl side chain in 3-position of the 2-benzofuran ring system by nucleophile substitution of a tosylate precursor [38][39][40][41][42]. The radiotracer properties of [ 18 F]18 (fluspidine, K i = 0.59 nM) [39,40] and [ 18 F]19 (K i = 1.4 nM) [41,42] Fig.…”

Distinctive In Vivo Kinetics of the New σ1 Receptor Ligands (R)-(+)- and (S)-(–)-18F-Fluspidine in Porcine Brain

“…We have recently synthesized 4 series of spirocyclic benzofurans (11)(12)(13)(14) and selected 4 derivatives (K i 5 0.59-1.4 nM) for 18 F labeling and evaluation as PET tracers (13)(14)(15)(16). Although all appear to be applicable for neuroimaging of s 1 Rs, a 2-fluoroethyl homolog, named 18 F-fluspidine, was most suitable (2).…”

Development of 18F-labeled radiotracers for neuroreceptor imaging with positron emission tomography

“…However, structural modifi cation was needed to introduce fl uorine in a suitable labeling position. Accordingly, various series of derivatives have been synthetized to select those with the highest affinity, selectivity, and in vitro metabolic stability [133][134][135][136][137][138] .…”