¹⁸F-Labeled 1,4-Dioxa-8-azaspiro[4.5]decane Derivative: Synthesis and Biological Evaluation of a σ₁ Receptor Radioligand with Low Lipophilicity as Potent Tumor Imaging Agent

Abstract

We report the syntheses and evaluation of series of novel piperidine compounds with low lipophilicity as σ1 receptor ligands. 8-(4-(2-Fluoroethoxy)benzyl)-1,4-dioxa-8-azaspiro[4.5]decane (5a) possessed high affinity (K(i) = 5.4 ± 0.4 nM) for σ1 receptors and selectivity for σ2 receptors (30-fold) and the vesicular acetylcholine transporter (1404-fold). [(18)F]5a was prepared using a one-pot, two-step labeling procedure in an automated synthesis module, with a radiochemical purity of >95%, and a specific activity of 25-45 GBq/μmol. Cellular association, biodistribution, and autoradiography with blocking experiments indicated specific binding of [(18)F]5a to σ1 receptors in vitro and in vivo. Small animal positron emission tomography (PET) imaging using mouse tumor xenograft models demonstrated a high accumulation in human carcinoma and melanoma. Treatment with haloperidol significantly reduced the accumulation of the radiotracer in tumors. These findings suggest that radiotracer with suitable lipophilicity and appropriate affinity for σ1 receptors could be used for tumor imaging.

Bridging from Brain to Tumor Imaging: (S)-(−)- and (R)-(+)-[18F]Fluspidine for Investigation of Sigma-1 Receptors in Tumor-Bearing Mice

“…Six human tumor cell lines were used to study the cellular accumulation ( Figure 2 ) of ( S )-(−)-[ 18 F]fluspidine and ( R )-(+)-[ 18 F]fluspidine in vitro following a published protocol [ 30 ].…”

“…Several PET radiotracers have been developed for imaging of Sig1R, such as [ 18 F]1-3-fluoropropyl-4-((4-cyanophenoxy)-methyl)piperidine ([ 18 F]FPS) [ 26 ], 1-(4-[ 18 F]fluorobenzyl)-4-[(tetrahydrofuran-2-yl)methyl]piperazine [ 27 ], [ 11 C]1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine ([ 11 C]SA4503) [ 28 ], [ 18 F]6-(3-fluoropropyl)-3-(2-(azepan-1-yl)ethyl)benzo[d]thiazol-2(3H)-one ([ 18 F]FTC-146) [ 29 ] and the 18 F-labeled 1,4-dioxa-8-azaspiro[4.5]decane derivative from our group [ 30 ]. Recently, we developed another two promising radioligands ( S )-(−)-[ 18 F]fluspidine and ( R )-(+)-[ 18 F]fluspidine [ 31 , 32 ], which both have been successfully used to image Sig1R in healthy mice [ 31 ] and piglets [ 33 ].…”

2-[18F]Fluoroethyl tosylate – a versatile tool for building18F-based radiotracers for positron emission tomography

“…23). 50,51 Radiolabeling of the spirocyclic piperidine was performed in an automated synthesizer using a one-pot two-step procedure without purification of [ 18 [ 18 F]fluoroethylation of diaryl-substituted acetanilides (Fig. 24).…”

18F‐Labeled benzylpiperazine derivatives as highly selective ligands for imaging σ1 receptor with positron emission tomography

“…( S )‐[ 18 F]fluspidine is another promising radiotracer, which is currently used to image the σ 1 receptors in patients with major depressive disorders and Huntington´s disease . In the past decades, we have put our efforts in the development of selective σ 1 receptor radioligands from several chemical classes, including 1‐piperonylpiperazine derivatives, 1,4‐dioxa‐8‐azaspiro[4.5]decane derivatives, 4‐phenylpiperidine‐4‐carbonitrile derivatives, spirocyclic piperidine derivatives, and 4‐[(tetrahydrofuran‐2‐yl)methyl]piperazine derivatives . The aim of the present study was to continue our search for an optimal 18 F‐labeled benzylpiperazine derivative with 3‐phenyl‐1‐(piperazin‐1‐yl)propan‐1‐one, 5‐phenyl‐1‐(piperazin‐1‐yl)pentan‐1‐one, or 1‐(3‐phenylpropyl)piperazine moiety for PET imaging of σ 1 receptors.…”

“…The distance between the basic nitrogen atom and the “primary hydrophobic region” or the “secondary hydrophobic region” were 0.25 to 0.39 nm and 0.6 to 1.0 nm, respectively . Later, it appears that smaller moiety with less lipophilicity can also serve as the “primary hydrophobic region”, indicating that the “primary hydrophobic region” in Glennon's pharmacophore model is more flexible . It was reported that compound 1 possessed low nanomolar affinity for σ 1 receptors ( K i (σ 1 ) = 1.8 ± 0.2 nM) and high subtype selectivity ( K i (σ 2 ) = 637 ± 15 nM, K i (σ 2 )/ K i (σ 1 ) = 354) .…”