title: Design and Investigation of a [18F]-Labeled Benzamide Derivative as a High Affinity Dual Sigma Receptor Subtype Radioligand for Prostate Tumor Imaging.
abstract: High overexpression of sigma (σ) receptors (σ1and σ2subtypes) 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 σ2receptor, 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 (σ1, 6.3 nM; σ2, 10.2 nM) was radiolabeled with fluorine-18 (18F) to give [18F]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 [18F]3a was localized to cell surface σ receptors, while ∼10% of [18F]3a was internalized within cells after incubation for 3.5 h. Serial PET imaging in mice bearing PC-3 tumors revealed that uptake of [18F]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 [18F]3a was σ receptor-mediated. Histology analysis confirmed similar expression of σ1and σ2in PC-3 tumors which was significantly greater than its expression in normal organs/tissues such as liver, kidney, and muscle. Metabolite studies revealed that >50% of radioactivity in PC-3 tumors at 30 min postinjection represented intact [18F]3a. Prominent σ receptor-specific uptake of [18F]3a in prostate tumors and its subsequent clear visualization with PET imaging indicate potential utility for the diagnosis of prostate carcinoma.
authors.affiliation: Center for Molecular Imaging, Department of Radiology, University of Michigan , Ann Arbor, Michigan 48109-2200, United States.|Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University , Xuzhou, Jiangsu 221004, China.
authors.forename: Dongzhi
authors.initials: D
authors.lastname: Yang
authors.affiliation: Department of Molecular Pharmacology, Physiology & Biotechnology, Brown University , Providence, Rhode Island 02912, United States.
authors.forename: Anthony
authors.initials: A
authors.lastname: Comeau
authors.affiliation: Department of Molecular Pharmacology, Physiology & Biotechnology, Brown University , Providence, Rhode Island 02912, United States.
authors.forename: Wayne D
authors.initials: WD
authors.lastname: Bowen
authors.affiliation: Department of Radiology, University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Mach
authors.affiliation: Center for Molecular Imaging, Department of Radiology, University of Michigan , Ann Arbor, Michigan 48109-2200, United States.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Ross
authors.affiliation: Center for Molecular Imaging, Department of Radiology, University of Michigan , Ann Arbor, Michigan 48109-2200, United States.
authors.forename: Hao
authors.initials: H
authors.lastname: Hong
authors.affiliation: Center for Molecular Imaging, Department of Radiology, University of Michigan , Ann Arbor, Michigan 48109-2200, United States.
authors.forename: Marcian E
authors.identifier: 0000-0002-6538-4661
authors.initials: ME
authors.lastname: Van Dort
mesh_terms: D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005462:Fluorine Radioisotopes / Q000737:chemistry*; D008024:Ligands; D008297:Male; D051379:Mice; D008819:Mice, Nude; D049268:Positron-Emission Tomography / Q000379:methods; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000188:drug therapy* / Q000378:metabolism; D011854:Radiochemistry / Q000379:methods; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017480:Receptors, sigma / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D001549:Benzamides; D005462:Fluorine Radioisotopes; D008024:Ligands; D019275:Radiopharmaceuticals; D017480:Receptors, sigma
keywords: PC-3 tumors; positron emission tomography; prostate cancer; sigma receptors