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Targeting Sigma Receptor-Binding Benzamides As in Vivo Diagnostic and Therapeutic Agents for Human Prostate Tumors1

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Targeting Sigma Receptor-Binding Benzamides As in Vivo Diagnostic and Therapeutic Agents for Human Prostate Tumors1 [CANCER RESEARCH 59, 4578–4583, September 15, 1999] Targeting Sigma Receptor-binding Benzamides as in Vivo Diagnostic and Therapeutic Agents for Human Prostate Tumors1 Christy S. John,2 Bertold J. Vilner, Brian C. Geyer, Terry Moody, and Wayne D. Bowen 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.] ABSTRACT currently limited by routine diagnostic modalities, such as magnetic resonance imaging, computed tomography, and ultrasound. The skel- Sigma receptors are known to be expressed in a variety of human etal metastases are routinely diagnosed with radionuclide skeletal tumor cells, including breast, neural, and melanoma tumors. A very high imaging. However, the soft tissue metastases and involvement of density (1.0–1.5 million receptors/cell) of sigma receptors was also re- ported in a human androgen-dependent prostate tumor cell line (LNCaP). pelvic lymph nodes cannot be accurately assessed with current tech- In this study, we show that a very high density of sigma receptors is also niques. Therefore, there is a need for a reliable noninvasive diagnostic expressed in an androgen-independent human prostate tumor cell line procedure to determine the lymphatic and soft tissue spread of pros- (DU-145). Pharmacological binding studies using the sigma-1-selective tate neoplasm. Accurate, early detection of prostate tumor and its 3 1 5 ligand [ H]( )-pentazocine showed a high-affinity binding (Kd 5.80 nM, metastases would improve patient management and outcome of ther- 5 3 111 Bmax 1800 fmol/mg protein). Similarly, binding studies with [ H]1,3-di- apy. Recently, the In-labeled murine antibody 7E11-C5.3-GYK o-tolylguanidine in the presence of dextrallorphan also showed a high- (conjugated to diethylenetriaminepentacetic acid linker chelator), affinity binding (K 5 15.71 nM, B 5 1930 fmol/mg protein). Radioio- d max which binds to prostate-specific antigen, was clinically studied and dinated benzamide N-[2-(1*-piperidinyl)ethyl]-3-[125I]iodo-4-methoxy- approved by the Food and Drug Administration under the commercial benzamide ([125I]PIMBA) was also shown to bind DU-145 cells in a dose-dependent manner. Three different radioiodinated benzamides, name “ProstaScint” for clinical staging and management of patients [125I]PIMBA, 4-[125I]iodo-N-[2-(1*-piperidinyl)ethyl]benzamide, and with prostate tumors (2–4). However, this product has several limi- 2-[125I]-N-(N-benzylpiperidin-4-yl)-2-iodobenzamide, were screened for tations, such as slow clearance of antibody from the plasma, high their potential to image human prostate tumors in nude mice bearing uptake in liver and intestine, production of human antimouse antibod- human prostate cells (DU-145) xenografts. All three compounds showed a ies in some patients, the need for repeat patient imaging up to 5 days fast clearance from the blood pool and a high uptake and retention in the postinjection, and the high cost of the drug. Radiolabeled small tumor. Therapeutic potential of nonradioactive PIMBA was studied using molecule(s) peptide or nonpeptide certainly would be preferred be- in vitro colonogenic assays. A dose-dependent inhibition of cell colony cause of their rapid clearance from the blood pool and normal organs. formation was found in two different human prostate cells. These results Sigma receptors are nonopiate, nondopaminergic, membrane- demonstrate the potential use of sigma receptor binding ligands in non- bound proteins that possess high affinity for haloperidol and various invasive diagnostic imaging of prostate cancer and its treatment. other neuroleptics (5). It is known that there are at least two sigma receptors subtypes, termed sigma-1 and sigma-2 (6). Sigma-1 sites INTRODUCTION can be selectively labeled by [3H](1)-pentazocine, whereas DTG3 is Prostate cancer is the male malignancy with the highest incidence a non-subtype-selective ligand for labeling both sigma-1 and sigma-2 3 rate in the Western hemisphere. It is the second leading cause of death sites (7, 8). Sigma-2 sites can be labeled with the use of [ H]DTG in in men in the United States, with the number of new incidences this the presence of dextrallorphan, which masks the labeling of sigma-1 year expected to be ;184,500. The total number of expected deaths sites (8). Sigma receptors are present not only in central nervous from prostate cancer this year is ;39,200. The current methods of system but also in other tissues, such as the liver, kidneys, lungs, diagnosis include digital rectal examination and prostate-specific an- gonads, and ovaries (9, 10). The endogenous sigma-ligand(s) are not tigen blood test. The effective treatment of prostate cancer requires known; however, progesterone has been suggested to be a candidate early detection and accurate staging of the disease. Generally, at the (11). The pharmacological significance of sigma receptor-binding clinical presentation, the majority of patients have disease that has sites remain elusive due to lack of functional and structural informa- extended beyond the prostate, i.e., local or distant metastases. Many tion. However, recently, the sigma-l binding site, a Mr 30,000 protein early-stage prostate tumors require androgen for survival, and thera- from guinea pig liver, was purified and cloned. The amino acid pies that are designed to interfere with steroid metabolism have been sequence of this protein showed no homology to any known mam- effective. Most prostate cancer patients, however, show relapse of malian proteins, but a partial homological resemblance with a fungal disease and acquire a more aggressive androgen-independent meta- protein involved in sterol synthesis was observed (12). static disease (1). There is no currently available curative therapy; On the basis of in vitro pharmacological binding studies with therefore, the development of new diagnostic imaging agents for tritiated ligands, we recently discovered that sigma receptors are accurate staging and new cytotoxic therapies is of utmost importance. expressed in high densities (1.0–1.5 million receptors/cell) on andro- The diagnosis of soft tissue primary or metastatic prostate carci- gen-dependent (LNCaP) human prostate tumor cells (13). Therefore, noma or even its residual/recurrent lesions after radical prostectomy is we reasoned that the compounds binding sigma receptors with a modest to high affinity could be potentially used for in vivo labeling Received 1/29/99; accepted 7/16/99. of such receptors, thereby enabling noninvasive imaging of human The costs of publication of this article were defrayed in part by the payment of page prostate tumor sites. In addition, sigma sites could be an attractive charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 This work was supported by National Cancer Institute Grant CA 58496 and by 3 The abbreviations used are: DTG, 1,3-di-o-tolylguanidine; PIMBA, N-[2-(19-piper- Research Corporation Technologies (Tucson, AZ). idinyl)ethyl]-3-iodo-4-methoxybenzamide; HPLC, high-performance liquid chromatogra- 2 To whom requests for reprints should be addressed, at 2300 I Street NW, 530 Ross phy; 2-[125I]BP, 2-[125I]-N-(N-benzylpiperidin-4-yl)-2-iodobenzamide; 4-[125I]PAB, Hall, Department of Biochemistry and Molecular Biology, The George Washington 4-[125I]iodo-N-[2-(19-piperidinyl)ethyl]benzamide; %ID, percentage injected dose; 2-IBP, University Medical Center, Washington, DC 20037. Phone: (202) 994-5031; Fax: (202) N-(N-benzylpiperidin-4-yl)-2-iodobenzamide; 4-IPAB, N-[2-(19-piperidinyl)ethyl]4-iodo- 994-8974; E-mail: [email protected]. benzamide. 4578 Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1999 American Association for Cancer Research. SIGMA RECEPTOR-BINDING BENZAMIDES FOR PROSTATE CANCER target not only for diagnostic imaging but also for therapeutic inter- residue was dissolved in methanol (400 ml) and injected into HPLC fitted with vention. Sigma receptors are also expressed in a variety of other a reverse-phase C18 column and eluted with methanol-Tris buffer (10 mM,pH human tumors, such as malignant melanoma (13, 14), non-small cell 5.5; 80:20, v/v). The retention time at a flow rate of 1.0 ml/min was ;9 min. lung carcinoma (15), breast (16, 17), and tumors of neural origin (18). The fractions containing the desired compound were pooled together and Pharmacological binding studies with membrane preparations from cospotted on TLC along with authentic nonradioactive and developed in CHCl :methanol (90:10). The R of nonradioactive and [125I]PIMBA was biopsied tumors tissue and the corresponding normal tissues have 3 f found to be 0.85 in the above solvent system. The chemical synthesis and indicated that sigma receptors are overexpressed with respect to structures of all three benzamides are shown in Fig. 1. normal tissue (19, 20). Sigma receptor-binding ligands have also shown the inhibition of Cell Culture proliferation in mammary adenocarcinoma (MCF-7 and MDA-MB- 231), colon carcinoma cells (LIM l2l5 and WIDr), melanoma cells, Human prostate tumor cells DU-145, PC-3 and LNCaP were purchased and neural tumor cells in culture (21, 22). These results have impli- from American Type Culture Collection (Manassas, VA) and cultured in serum cated that sigma binding sites may play an important role in cell supplemented DMEM containing 10% heat-inactivated fetal bovine serum growth, differentiation, and cell proliferation as well. Here, we eval- (Life Technologies, Inc.) at 37°C. The cells were adherent and split 1:5 ratio uated the noninvasive imaging potential of three radioiodinated ben- using trypsin-EDTA (Life Technologies, Inc.).
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