title: Radiosynthesis, biodistribution and imaging of [11C]YM155, a novel survivin suppressant, in a human prostate tumor-xenograft mouse model.
abstract: BACKGROUND
  Sepantronium bromide (YM155) is an antitumor drug in development and is a first-in-class chemical entity, which is a survivin suppressant. We developed a radiosynthesis of [(11)C]YM155 to non-invasively evaluate its tissue and tumor distribution in mice bearing human prostate tumor xenografts.
  
  
  METHODS
  Methods utilizing [(11)C]acetyl chloride and [(11)C]methyl triflate, both accessible with automated radiosynthesis boxes, were evaluated. The O-methylation of ethanolamine-alkolate with [(11)C]methyl triflate proved to be the key development toward a rapid and efficient process. The whole-body distribution of [(11)C]YM155 in PC-3 xenografted mice was examined using a planar positron imaging system (PPIS).
  
  
  RESULTS
  Sufficient quantities of radiopharmaceutical grade [(11)C]YM155 were produced for our PET imaging and distribution studies. The decay corrected (EOB) radiochemical yield was 16-22%, within a synthesis time of 47 min. The radiochemical purity was higher than 99%, and the specific activity was 29-60 GBq/μmol (EOS). High uptake levels of radioactivity (%ID/g, mean±SE) were observed in tumor (0.0613±0.0056), kidneys (0.0513±0.0092), liver (0.0368±0.0043) and cecum (0.0623±0.0070). The highest tumor uptake was observed at an early time point (from 10 min after) following injection. Tumor-to-blood and tumor-to-muscle uptake ratios of [(11)C]YM155, at 40 min after injection, were 26.5 (±2.9) and 25.6 (±3.6), respectively.
  
  
  CONCLUSIONS
  A rapid method for producing a radiopharmaceutical grade [(11)C]YM155 was developed. An in vivo distribution study using PPIS showed high uptake of [(11)C]YM155 in tumor tissue. Our methodology may facilitate the evaluation and prediction of response to YM155, when given as an anti-cancer agent.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Japan. yoshihiro.murakami@astellas.com
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Murakami
authors.forename: Takahiro
authors.initials: T
authors.lastname: Matsuya
authors.forename: Aya
authors.initials: A
authors.lastname: Kita
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yamanaka
authors.forename: Akihiro
authors.initials: A
authors.lastname: Noda
authors.forename: Keisuke
authors.initials: K
authors.lastname: Mitsuoka
authors.forename: Takahito
authors.initials: T
authors.lastname: Nakahara
authors.forename: Sosuke
authors.initials: S
authors.lastname: Miyoshi
authors.forename: Shintaro
authors.initials: S
authors.lastname: Nishimura
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002250:Carbon Radioisotopes; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D009285:Naphthoquinones / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D049268:Positron-Emission Tomography / Q000379:methods*; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology*; D011854:Radiochemistry / Q000379:methods*; D000077022:Survivin; D014018:Tissue Distribution; D051598:Whole Body Imaging
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D002250:Carbon Radioisotopes; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D009285:Naphthoquinones; D000077022:Survivin; C523798:sepantronium