title: Synthesis and evaluation of a new vesamicol analog o-[(11)C]methyl-trans-decalinvesamicol as a PET ligand for the vesicular acetylcholine transporter.
abstract: BACKGROUND
  We focused on the vesicle acetyl choline transporter (VAChT) as target for early diagnosis of Alzheimer's diseases because the dysfunction of the cholinergic nervous system is closely associated with the symptoms of AD, such as problem in recognition, memory, and learning. Due to its low binding affinity for the sigma receptors (σ-1 and σ-2), o-methyl-trans-decalinvesamicol (OMDV) demonstrated a high binding affinity and selectivity for vesicular acetyl choline transporter (VAChT). [(11)C]OMDV was prepared and investigated the potential as a new PET ligand for VAChT imaging through in vivo evaluation.
  
  
  METHODS
  [(11)C]OMDV was prepared by a palladium-promoted cross-coupling reaction using [(11)C]methyl iodide, with a radiochemical yield of 60-75%, a radiochemical purity of greater than 98%, and a specific activity of 5-10 TBq/mmol 30 min after EOB. In vivo biodistribution study of [(11)C]OMDV in blood, brain regions and major organs of rats was performed at 2, 10, 30 and 60 min post-injection. In vivo blocking study and PET-CT imaging study were performed to check the binding selectivity of [(11)C]OMDV for VAChT.
  
  
  RESULTS
  In vivo studies demonstrated [(11)C]OMDV passage through the blood-brain barrier (BBB) and accumulation in the rat brain. The regional brain accumulation of [(11)C]OMDV was significantly inhibited by co-administration of vesamicol. In contrast, brain accumulation of [(11)C]OMDV was not significantly altered by co-administration of (+)-pentazocine, a selective σ-1 receptor ligand, or (+)-3-(3-hydroxyphenyl)-N-propylpiperidine [(+)-3-PPP], a σ-1 and σ-2 receptor ligand. PET-CT imaging revealed inhibition of [(11)C]OMDV accumulation in the brain by co-administration of vesamicol.
  
  
  CONCLUSIONS
  [(11)C]OMDV selectively binds to VAChT with high affinity in the rat brain in vivo, and that [(11)C]OMDV may be utilized in the future as a specific VAChT ligand for PET imaging.
authors.affiliation: Division of Tracer Kinetics, Advanced Science Research Center, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan. ykitamu@staff.kanazawa-u.ac.jp.
authors.forename: Yoji
authors.initials: Y
authors.lastname: Kitamura
authors.affiliation: Division of Tracer Kinetics, Advanced Science Research Center, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan. t-kozaka@staff.kanazawa-u.ac.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kozaka
authors.affiliation: Division of Tracer Kinetics, Advanced Science Research Center, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Miwa
authors.affiliation: Division of Tracer Kinetics, Advanced Science Research Center, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan.|Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan.
authors.forename: Izumi
authors.initials: I
authors.lastname: Uno
authors.affiliation: National Institute of Nuclear Medicine and Allied Sciences, Bangladesh Atomic Energy Commission, BSM Medical University Campus, Block-D, 7th-10th floor, Shahbagh, Dhaka, 1000, Bangladesh.
authors.forename: Mohammad Anwar-Ul
authors.initials: MA
authors.lastname: Azim
authors.affiliation: Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Ogawa
authors.affiliation: Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Taki
authors.affiliation: Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan.
authors.forename: Seigo
authors.initials: S
authors.lastname: Kinuya
authors.affiliation: Division of Tracer Kinetics, Advanced Science Research Center, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan. shiba@med.kanazawa-u.ac.jp.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Shiba
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D002250:Carbon Radioisotopes; D060326:Chemistry Techniques, Synthetic; D008024:Ligands; D008297:Male; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D050494:Vesicular Acetylcholine Transport Proteins / Q000378:metabolism*
chemical_list: D002250:Carbon Radioisotopes; D008024:Ligands; D010880:Piperidines; D050494:Vesicular Acetylcholine Transport Proteins; C000611878:o-methyldecalinvesamicol
keywords: PET; Presynaptic cholinergic neurons; Vesamicol analogs; Vesicular acetylcholine transporter