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High overexpression of sigma (σ) receptors (σ 1 and σ 2 subtypes) in a variety of human solid tumors has prompted the development of σ receptor-targeting radioligands, as imaging agents for tumor detection. A majority of these radioligands to date target the σ 2 receptor, a potential marker of tumor proliferative status. The identification of approximately equal proportions of both σ receptor subtypes in prostate tumors suggests that a high affinity, dual σ receptor-targeting radioligand could potentially provide enhanced tumor targeting efficacy in prostate cancer. To accomplish this goal, we designed a series of ligands which bind to both σ receptor subtypes with high affinity. Ligand 3a in this series, displaying optimal dual σ receptor subtype affinity (σ 1 , 6.3 nM; σ 2 , 10.2 nM) was radiolabeled with fluorine-18 ( 18 F) to give [ 18 F]3a and evaluated as a σ receptor-targeting radioligand in the mouse PC-3 prostate tumor model. Cellular assays with PC-3 cells demonstrated that a major proportion of [ 18 F]3a was localized to cell surface σ receptors, while ∼10% of [ 18 F]3a was internalized within cells after incubation for 3.5 h. Serial PET imaging in mice bearing PC-3 tumors revealed that uptake of [ 18 F]3a was 1.6 ± 0.8, 4.4 ± 0.3, and 3.6 ± 0.6% ID/g (% injection dose per gram) in σ receptor-positive prostate tumors at 15 min, 1.5 h, and 3.5 h postinjection, respectively (n = 3) resulting in clear tumor visualization. Blocking studies conducted with haloperidol (a nonselective inhibitor for both σ receptor subtypes) confirmed that the uptake of [ 18 F]3a was σ receptor-mediated. Histology analysis confirmed similar expression of σ 1 and σ 2 in PC-3 tumors which was significantly greater than its expression in normal organs/tissues such as liver, kidney, and muscle. Metabolite studies revealed that &gt;50% of radioactivity in PC-3 tumors at 30 min postinjection represented intact [ 18 F]3a. Prominent σ receptor-specific uptake of [ 18 F]3a in prostate tumors and its subsequent clear visualization with PET imaging indicate potential utility for the diagnosis of prostate carcinoma.

molecular pharmaceutics

Design and Investigation of a [<sup>18</sup>F]-Labeled Benzamide Derivative as a High Affinity Dual Sigma Receptor Subtype Radioligand for Prostate Tumor Imaging

Design and Investigation of a [18F]-Labeled Benzamide Derivative as a High Affinity Dual Sigma Receptor Subtype Radioligand for Prostate Tumor Imaging

Design and Investigation of a [¹⁸F]-Labeled Benzamide Derivative as a High Affinity Dual Sigma Receptor Subtype Radioligand for Prostate Tumor Imaging