title: Preparation and evaluation of an astatine-211-labeled sigma receptor ligand for alpha radionuclide therapy.
abstract: BACKGROUND
  Sigma receptors are overexpressed in a variety of human tumors, making them potential targets for radionuclide receptor therapy. We have previously synthesized and evaluated (131)I-labeled (+)-2-[4-(4-iodophenyl)piperidino]cyclohexanol [(+)-[(131)I]pIV], which has a high affinity for sigma receptors. Therefore, (+)-[(131)I]pIV significantly inhibited tumor cell proliferation in tumor-bearing mice. In the present study, we report the synthesis and the in vitro and in vivo characterization of (+)-[(211)At]pAtV, an (211)At-labeled sigma receptor ligand, that has potential use in alpha-radionuclide receptor therapy.
  
  
  METHODS
  The radiolabeled sigma receptor ligand (+)-[(211)At]pAtV was prepared using a standard halogenation reaction generating a 91% radiochemical yield with 98% purity after HPLC purification. The partition coefficient of (+)-[(211)At]pAtV was measured. Cellular uptake experiments and in vivo biodistribution experiments were performed using a mixed solution of (+)-[(211)At]pAtV and (+)-[(125)I]pIV; the human prostate cancer cell line DU-145, which expresses high levels of the sigma receptors, and DU-145 tumor-bearing mice.
  
  
  RESULTS
  The lipophilicity of (+)-[(211)At]pAtV was similar to that of (+)-[(125)I]pIV. DU-145 cellular uptake and the biodistribution patterns in DU-145 tumor-bearing mice at 1h post-injection were also similar between (+)-[(211)At]pAtV and (+)-[(125)I]pIV. Namely, (+)-[(211)At]pAtV demonstrated high uptake and retention in tumor via binding to sigma receptors.
  
  
  CONCLUSIONS
  These results indicate that (+)-[(211)At]pAtV could function as an new agent for alpha-radionuclide receptor therapy.
authors.affiliation: Graduate School of Medical Sciences, Kanazawa University, Kanazawa 920-1192, Japan; Institute for Frontier Science Initiative, Kanazawa University, Kanazawa 920-1192, Japan. Electronic address: kogawa@p.kanazawa-u.ac.jp.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Ogawa
authors.affiliation: Graduate School of Medical Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Mizuno
authors.affiliation: Graduate School of Medical Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
authors.forename: Kohshin
authors.initials: K
authors.lastname: Washiyama
authors.affiliation: Advanced Science Research Center, Kanazawa University, Kanazawa 920-8640, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Shiba
authors.affiliation: Graduate School of Science, Osaka University, Osaka 560-0043, Japan.
authors.forename: Naruto
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Advanced Science Research Center, Kanazawa University, Kanazawa 920-8640, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kozaka
authors.affiliation: Medical Radioisotope Application Group, Japan Atomic Energy Agency, Takasaki, 370-1292 Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Graduate School of Science, Osaka University, Osaka 560-0043, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shinohara
authors.affiliation: Graduate School of Medical Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Odani
mesh_terms: D000512:Alpha Particles / Q000627:therapeutic use*; D000818:Animals; D001246:Astatine / Q000627:therapeutic use*; D001692:Biological Transport; D045744:Cell Line, Tumor; D003511:Cyclohexanols / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use*; D004355:Drug Stability; D006801:Humans; D007553:Isotope Labeling; D008024:Ligands; D008297:Male; D051379:Mice; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use*; D017480:Receptors, sigma / Q000378:metabolism*; D013237:Stereoisomerism; D014018:Tissue Distribution
chemical_list: C502476:2-(4-(4-iodophenyl) piperidino)cyclohexanol; D003511:Cyclohexanols; D008024:Ligands; D010880:Piperidines; D017480:Receptors, sigma; D001246:Astatine
keywords: Alpha therapy; Astatine; Sigma receptor; Tumor