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Targeting Sigma Receptor-binding Benzamides as in Vivo Diagnostic and Therapeutic Agents for Human Prostate Tumors¹

Department of Biochemistry and Molecular Biology, The George Washington University Medical Center, Washington, DC 20037 [C. S. J., B. C. G.]; Unit on Receptor Biochemistry and Pharmacology, Laboratory of Medicinal Chemistry, National Institutes of Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892 [B. J. V., W. D. B.]; and Cell and Cancer Biology Department, Medicine Branch, National Cancer Institute, Rockville, Maryland 20850 [T. M.]

Sigma receptors are known to be expressed in a variety of human tumor cells, including breast, neural, and melanoma tumors. A very high density (1.0–1.5 million receptors/cell) of sigma receptors was also reported in a human androgen-dependent prostate tumor cell line (LNCaP). In this study, we show that a very high density of sigma receptors is also expressed in an androgen-independent human prostate tumor cell line (DU-145). Pharmacological binding studies using the sigma-1-selective ligand [³H](+)-pentazocine showed a high-affinity binding (K_d = 5.80 nM, B_max = 1800 fmol/mg protein). Similarly, binding studies with [³H]1,3-di-o-tolylguanidine in the presence of dextrallorphan also showed a high-affinity binding (K_d = 15.71 nM, B_max = 1930 fmol/mg protein). Radioiodinated benzamide N-[2-(1'-piperidinyl)ethyl]-3-[¹²⁵I]iodo-4-methoxy-benzamide ([¹²⁵I]PIMBA) was also shown to bind DU-145 cells in a dose-dependent manner. Three different radioiodinated benzamides, [¹²⁵I]PIMBA, 4-[¹²⁵I]iodo-N-[2-(1'-piperidinyl)ethyl]benzamide, and 2-[¹²⁵I]-N-(N-benzylpiperidin-4-yl)-2-iodobenzamide, were screened for their potential to image human prostate tumors in nude mice bearing human prostate cells (DU-145) xenografts. All three compounds showed a fast clearance from the blood pool and a high uptake and retention in the tumor. Therapeutic potential of nonradioactive PIMBA was studied using in vitro colonogenic assays. A dose-dependent inhibition of cell colony formation was found in two different human prostate cells. These results demonstrate the potential use of sigma receptor binding ligands in noninvasive diagnostic imaging of prostate cancer and its treatment.

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