Evaluation of Spirocyclic 3-(3-Fluoropropyl)-2-benzofurans as σ₁ Receptor Ligands for Neuroimaging with Positron Emission Tomography

Abstract

A series of various N-substituted 3-(3-fluoropropyl)-3H-spiro[[2]benzofuran-1,4'-piperidines] (7) has been synthesized. In receptor binding studies, the N-benzyl derivative 7a (WMS-1813) revealed extraordinarily high sigma(1) receptor affinity (K(i) = 1.4 nM) and excellent sigma(1)/sigma(2) selectivity (>600 fold). In vitro biotransformation of 7a with rat liver microsomes led to three main metabolites. N-Debenzylation was inhibited by introduction of an N-phenylethyl residue (7 g). The PET tracer [(18)F]7a was synthesized by nucleophilic substitution of the tosylate 13 with K[(18)F]F-K222-carbonate complex. The decay corrected radiochemical yield of [(18)F]7a was 35-48% with a radiochemical purity of >99.5% and a specific activity of 150-238 GBq/micromol. The radiotracer properties were evaluated in female CD-1 mice by organ distribution and ex vivo brain autoradiography. The radiotracer uptake in the brain was fast and sufficient, with values of approximately 4% injected dose per gram. Target specificity of [(18)F]7a was validated in blocking studies by preapplication of haloperidol, and significant reduction in the uptake of radioactivity was observed in the brain and peripheral organs expressing sigma(1) receptors.

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

“…Organ distribution studies in mice using the corresponding fluorine-18-labeled radiotracer [ 18 F]1 demonstrated that this class of derivatives offers excellent potential for neuroimaging of central s 1 receptors with PET. [40] Next, we investigated the effects of replacing the 3-fluoropropyl moiety of 1 with a 2-fluoroethyl residue. This structural modification resulted in the more potent and selective ligand 2 (K i (s 1 ) = 0.59 nm; K i (s 2 ) = 785 nm).…”

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] .…”