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

We report the syntheses and evaluation of series of novel piperidine compounds with low lipophilicity as sigma(1) receptor ligarids. 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 sigma(1) receptors and selectivity for sigma(2) receptors (30-fold) and the vesicular acetylcholine transporter (1404-fold). [F-18]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/mu mol. Cellular association, biodistribution, and autoradiography with blocking experiments indicated specific binding of [F-18]5a to sigma(1) receptors in vitro and in vivo. Small annual 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 sigma(1) receptors could be used for tumor imaging.