title: Synthesis, in vitro binding, and tissue distribution of radioiodinated 2-[125I]N-(N-benzylpiperidin-4-yl)-2-iodo benzamide, 2-[125I]BP: a potential sigma receptor marker for human prostate tumors.
abstract: The preclinical evaluation of a sigma receptor-specific radiopharmaceutical that binds to human prostate tumor cells with a high affinity is described. We have synthesized and radioiodinated 2-[125I]-N-(N-benzylpiperidin-4-yl)-2-iodobenzamide (2-[125I]BP) that possesses high affinity for both sigma-1 and sigma-2 receptor subtypes that are expressed on a variety of tumor cells. 2-IBP was synthesized, purified and characterized by routine spectroscopic and analytical methods. Radioiodination was accomplished using an oxidative iododestannylation reaction in the presence of chloramine T in high yields (76%-93%) with a very high-specific activity (1700-1900 Ci/mmol). The in vitro competition binding studies of 2-[125I]BP with various sigma receptor ligands in LnCAP human prostate tumor cells showed a dose-dependent saturable binding. The inhibition constants (Ki, nM) for binding of 2-[125I]BP to human prostate tumor cells for 4-IBP, haloperidol and 2-IBP were 4.09, 6.34 and 1.6 nM, respectively. The clearance of 2-[125I]BP, in Sprague-Dawley rats, was rapid from the blood pool, other normal tissues and the total body. Tissue distribution studies in nude mice bearing human prostate tumor (DU-145) also showed a fast clearance from normal organs. The tumor had the highest percentage of injected dose per gram (%ID/g) of all tissues at 4 h as well as 24 h (2.0 +/- 0.05 and 0.147 +/- 0.038 ID/g, respectively) postinjection. The in vivo receptor binding specificity was demonstrated using haloperidol (a known high-affinity sigma receptor ligand). A significant decrease (> 50%, p = 0.001) was observed in tumor concentration when haloperidol was used as a blocking agent. The high affinity of 2-[125I]BP for sgma receptor-binding sites, its fast in vivo clearance from normal organs and its high uptake and retention in tumor implies that 2-[123I]BP or 2-[131I]BP may be a promising tracer for noninvasive imaging of human prostate tumors.
authors.affiliation: Department of Radiology, George Washington University Medical Center, Washington, DC 20037, USA. johncs@gwis2.circ.gwu.edu
authors.forename: C S
authors.initials: CS
authors.lastname: John
authors.forename: M E
authors.initials: ME
authors.lastname: Gulden
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: W D
authors.initials: WD
authors.lastname: Bowen
authors.forename: J G
authors.initials: JG
authors.lastname: McAfee
authors.forename: M L
authors.initials: ML
authors.lastname: Thakur
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D001667:Binding, Competitive; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D007202:Indicators and Reagents; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics*; D007700:Kinetics; D008297:Male; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000032:analysis* / Q000378:metabolism; D014018:Tissue Distribution / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D001549:Benzamides; D007202:Indicators and Reagents; D007457:Iodine Radioisotopes; C113309:N-(N-benzylpiperidin-4-yl)-2-iodobenzamide; D010880:Piperidines; D019275:Radiopharmaceuticals; D017480:Receptors, sigma; D006220:Haloperidol