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A series of N-(1-benzylpiperidin-4-yl)phenylacetamide derivatives was synthesized and evaluated for affinity at sigma1 and sigma2 receptors. Most of these compounds showed a high affinity for sigma1 receptors and a low to moderate affinity for sigma2 receptors. The unsubstituted compound N-(1-benzylpiperidin-4-yl)phenylacetamide, 1, displayed a high affinity and selectivity for sigma1 receptors (Ki values of 3.90 nM for sigma1 receptors and 240 nM for sigma2 receptors). The influence of substitutions on the phenylacetamide aromatic ring on binding at both the sigma1 and sigma2 receptor has been examined through Hansch-type quantitative structure-activity relationship (QSAR) studies. In general, all 3-substituted compounds, except for the OH group, had a higher affinity for both sigma1 and sigma2 receptors when compared with the corresponding 2- and 4-substituted analogues. The selectivity for sigma1 receptors displayed a trend of 3 > 2 approximately 4 for Cl, Br, F, NO2, and OMe substituted analogues. Halogen substitution on the aromatic ring generally increased the affinity for sigma2 receptors while maintaining a similar affinity for sigma1 receptors. Substitution with electron-donating groups, such as OH, OMe, or NH2, resulted in weak or negligible affinity for sigma2 receptors and a moderate affinity for sigma1 receptors. The 2-fluoro-substituted analogue, 11, exhibited the highest selectivity for sigma1 receptors among all compounds tested, with a Ki value of 3.56 nM for sigma1 receptors and 667 nM for sigma2 receptors. Compounds 1, 5, 9, 11, and 20 had no affinity for dopamine D2 (IC50 > 10 000 nM) and D3 (IC50 > 10 000 nM) receptors. The nanomolar binding affinity and high selectivity for sigma1 receptors suggest that these compounds may be developed as potential radiotracers for positron emission tomography or single photon emission computerized tomography imaging studies.

Thymomas are lacking in malignant cytological features. Their staging is defined by the invasiveness of the tumour. This study aimed to analyse the uptake patterns of fluorine-18 fluorodeoxyglucose (FDG) in thymomas of different stages. FDG positron emission tomography (PET) scan was performed in 12 patients suspected of having thymoma and in nine controls. Qualitative visual interpretation was used to detect the foci with FDG uptake higher than that of normal mediastinum. Tumour/lung ratio (TLR) was calculated from the counts of ROIs over the mass and over comparable normal lung tissue in thymoma patients. Mediastinum/lung ratio (MLR) was calculated from the counts of ROIs over the anterior mediastinum and lung in controls. The PET scan patterns of distribution of foci with FDG uptake and TLRs were correlated with the computed tomography (CT) or magnetic resonance imaging (MRI) findings, and staging of the thymomas. Thymectomy was performed in ten patients and thoracoscopy was done in two patients. The results revealed ten thymomas (two stage I tumours, two stage II, four stage III and two stage IV, according to the Masaoka classification), and two cases of thymic hyperplasia associated with myasthenia gravis. Myasthenia gravis was also noted in four thymoma patients. FDG studies showed (a) diffuse uptake in the widened anterior mediastinum in patients with thymic hyperplasia, (b) confined focal FDG uptake in the non-invasive or less invasive, stage I and II thymomas, and (c) multiple discrete foci of FDG uptake in the mediastinum and thoracic structures in stage III and IV advanced invasive thymomas. The thymomas had the highest TLRs, followed by the TLRs of thymic hyperplasia and the MLRs of control subjects (P <0.005). No significant difference was found between thymomas in different stages or between thymomas with and thymomas without myasthenia gravis. In comparison with CT and/or MRI, FDG-PET detected more lesions in patients with invasive thymomas and downgraded the staging of thymoma in four patients. Our preliminary results suggest that FDG-PET is useful in the assessment of the invasiveness of thymomas, and may have the potential to differentiate thymomas from thymic hyperplasia.

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