Search

Wereport the syntheses and evaluation of series of novel piperidinecompounds with low lipophilicity as σ1receptor ligands.8-(4-(2-Fluoroethoxy)benzyl)-1,4-dioxa-8-azaspiro[4.5]decane(5a) possessed high affinity (Ki= 5.4 ± 0.4 nM) for σ1receptors andselectivity for σ2receptors (30-fold) and the vesicularacetylcholine transporter (1404-fold). [18F]5awas prepared using a one-pot, two-step labeling procedure in anautomated 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 indicatedspecific binding of [18F]5atoσ1receptors in vitro and in vivo. Small animal positronemission tomography (PET) imagingusing mouse tumor xenograft models demonstrated a high accumulationin human carcinoma and melanoma. Treatment with haloperidol significantlyreduced the accumulation of the radiotracer in tumors. These findingssuggest that radiotracer with suitable lipophilicity and appropriateaffinity for σ1receptors could be used for tumorimaging. [ABSTRACT FROM AUTHOR]

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 σ1receptor affinity (Ki= 1.4 nM) and excellent σ1/σ2selectivity (>600fold). In vitro biotransformation of 7awith rat liver microsomes led to three main metabolites. N-Debenzylation was inhibited by introduction of an N-phenylethyl residue (7g). The PET tracer [18F]7awas synthesized by nucleophilic substitution of the tosylate 13with K[18F]F-K222-carbonate complex. The decay corrected radiochemical yield of [18F]7awas 35−48% with a radiochemical purity of >99.5% and a specific activity of 150−238 GBq/μmol. 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 ∼4% injected dose per gram. Target specificity of [18F]7awas 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 σ1receptors. [ABSTRACT FROM AUTHOR]