title: Development of [11C]/[3H]THK-5351 - A potential novel carbon-11 tau imaging PET radioligand.
abstract: BACKGROUND
  Due to the rise in the number of patients with dementia the imperative for finding new diagnostic and treatment options becomes ever more pressing. While significant progress has been made in PET imaging of Aβ aggregates both in vitro and in vivo, options for imaging tau protein aggregates selectively are still limited. Based on the work previously published by researchers from the Tohoku University, Japan, that resulted in the development of [18F]THK-5351, we have undertaken an effort to develop a carbon-11 version of the identical structure - [11C]THK-5351. In parallel, THK-5351 was also labeled with tritium ([3H]THK-5351) for use in in vitro autoradiography (ARG).
  
  
  METHODS
  The carbon-11 labeling was performed starting with di-protected enantiomeric pure precursor - tert-butyl 5-(6-((2S)-3-fluoro-2-(tetrahydro-2H-pyran-2-yloxy)propoxy)quinolin-2-yl)pyridin-2-yl carbamate, which was reacted with [11C]MeI, using DMF as the solvent and NaH as base, followed by deprotection with trifluoroacetic acid/water mixture, resulting in enantiomerically pure carbon-11 radioligand, [11C]THK-5351 - (S)-1-fluoro-3-(2-(6-([11C]methylamino)pyridin-3-yl)quinolin-6-yloxy)propan-2-ol. Tritium labeling and purification of [3H]THK-5351 were undertaken using similar approach, resulting in [3H]THK-5351 with RCP >99.8% and specific radioactivity of 1.3GBq/μmol.
  
  
  RESULTS
  [11C]THK-5351 was produced in good yield (1900±355MBq), specific radioactivity (SRA) (361±119GBq/μmol at EOS+20min) and radiochemical purity (RCP) (>99.8%), with enantiomeric purity of 98.7%. [3H]THK-5351 was evaluated for ARG of tau binding in post-mortem human brain tissue using cortical sections from one AD patient and one control subject. [3H]THK-5351 binding density was higher in the AD patient compared to the control subject, the binding was displaced by unlabeled THK-5351 confirming specific [3H]THK-5351 binding.
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Center for Psychiatric Research, Stockholm, Sweden. Electronic address: vladimir.stepanov@ki.se.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Stepanov
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Center for Psychiatric Research, Stockholm, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Svedberg
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Center for Psychiatric Research, Stockholm, Sweden.
authors.forename: Zhisheng
authors.initials: Z
authors.lastname: Jia
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Center for Psychiatric Research, Stockholm, Sweden.
authors.forename: Raisa
authors.initials: R
authors.lastname: Krasikova
authors.affiliation: Karolinska Institutet, Department of Neurobiology, Center for Alzheimer Research, Stockholm, Sweden.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Lemoine
authors.affiliation: Department of Pharmacology, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Nobujuki
authors.initials: N
authors.lastname: Okamura
authors.affiliation: Department of Pharmacology, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Shozo
authors.initials: S
authors.lastname: Furumoto
authors.affiliation: Karolinska Institutet, Department of Neuroscience, Science for Life Laboratory, Stockholm.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Mitsios
authors.affiliation: Karolinska Institutet, Department of Neuroscience, Science for Life Laboratory, Stockholm.
authors.forename: Jan
authors.initials: J
authors.lastname: Mulder
authors.affiliation: Department of Chemistry, Uppsala University, Uppsala, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Långström
authors.affiliation: Karolinska Institutet, Department of Neurobiology, Center for Alzheimer Research, Stockholm, Sweden.
authors.forename: Agneta
authors.initials: A
authors.lastname: Nordberg
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Center for Psychiatric Research, Stockholm, Sweden.
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
mesh_terms: D000631:Aminopyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002250:Carbon Radioisotopes; D006801:Humans; D008024:Ligands; D049268:Positron-Emission Tomography / Q000379:methods*; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D011854:Radiochemistry; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D000631:Aminopyridines; D002250:Carbon Radioisotopes; D008024:Ligands; D011804:Quinolines; C000608225:THK5351; D016875:tau Proteins
keywords: Autoradiography; Carbon-11; Pet; Proteinopathy; Tau imaging; Tritium