title: Development of a PET radioligand for the central 5-HT1B receptor: radiosynthesis and characterization in cynomolgus monkeys of eight radiolabeled compounds.
abstract: BACKGROUND
  The serotonin 1B (5-HT(1B)) receptor has been implicated in several psychiatric disorders and is a potential pharmacological target in the treatment of depression. The aim of this study was to develop a radioligand for positron emission tomography (PET) imaging of the 5-HT(1B) receptor in the primate brain in vivo.
  
  
  METHODS
  Eight carboxamide radioligands (1-8) from three different core structures were radiolabeled with carbon-11 employing N-methylation with [(11)C]methyl triflate on the piperazine structural moiety. In vivo PET evaluation of each radioligand was performed in cynomolgus monkeys and included analysis of radioactive metabolites measured in plasma using high-performance liquid chromatography.
  
  
  RESULTS
  In a total of 12 radiosynthesis of the eight radioligands, the mean decay corrected yield was 11%, and the mean specific radioactivity was 299 GBq/μmol (8075 Ci/mmol) at time of administration. Of the eight tested candidates, [(11)C]6 demonstrated the most promising in vivo characteristics, showing high binding in 5-HT(1B) receptor-rich regions and low binding in the cerebellum. When inspecting data from all eight compounds, lipophilicity appeared as a physicochemical property that could be related to favorable in vivo imaging characteristics.
  
  
  CONCLUSIONS
  Candidate [(11)C]6, i.e., [(11)C]AZ10419369, exhibited high binding potentials in regions known to contain 5-HT(1B) receptors and was nominated for further preclinical characterization and PET examination in human subjects.
authors.affiliation: Psychiatry Section, Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital, SE-17176 Stockholm, Sweden. j.d.andersson@ki.se
authors.forename: Jan D
authors.initials: JD
authors.lastname: Andersson
authors.forename: M Edward
authors.initials: ME
authors.lastname: Pierson
authors.forename: Sjoerd J
authors.initials: SJ
authors.lastname: Finnema
authors.forename: Balázs
authors.initials: B
authors.lastname: Gulyás
authors.forename: Richard
authors.initials: R
authors.lastname: Heys
authors.forename: Charles S
authors.initials: CS
authors.lastname: Elmore
authors.forename: Lars
authors.initials: L
authors.lastname: Farde
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
mesh_terms: D000577:Amides / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002250:Carbon Radioisotopes; D006801:Humans; D007553:Isotope Labeling; D008024:Ligands; D008252:Macaca fascicularis; D049268:Positron-Emission Tomography / Q000379:methods*; D011854:Radiochemistry / Q000379:methods*; D044302:Receptor, Serotonin, 5-HT1B / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D000577:Amides; D002250:Carbon Radioisotopes; D008024:Ligands; D044302:Receptor, Serotonin, 5-HT1B