title: Preclinical evaluation of [18F]2FNQ1P as the first fluorinated serotonin 5-HT6 radioligand for PET imaging.
abstract: OBJECTIVE
  Brain serotonin 6 receptor (5-HT6) is one of the most recently identified serotonin receptors. It is a potent therapeutic target for psychiatric and neurological diseases, e.g. schizophrenia and Alzheimer's disease. Since no specific fluorinated radioligand has yet been successfully used to study this receptor by positron emission tomography (PET) neuroimaging, the objective of the present study was to study the first 5-HT6 (18)F-labelled radiotracer.
  
  
  METHODS
  2FNQ1P, inspired by the quinolone core of a previous radiotracer candidate, GSK215083, was selected according its 5-HT6 affinity and selectivity and was radiolabelled by (18)F nucleophilic substitution. The cerebral distribution of [(18)F]2FNQ1P was studied in vivo in rats, cats and macaque monkeys.
  
  
  RESULTS
  The chemical and radiochemical purities of [(18)F]2FNQ1P were >98 %. In rats, in vitro competition with the 5-HT6 antagonist, SB258585, revealed that the radioligand was displaced dose dependently. Rat microPET studies showed low brain uptake of [(18)F]2FNQ1P, reversed by the P-glycoprotein inhibitor, cyclosporin. On the contrary, PET scans in cats showed good brain penetration and specific striatal binding blocked after pretreatment with unlabelled 2FNQ1P. PET scans in macaque monkeys confirmed high specific binding in both cortical and subcortical regions, specifically decreased by pretreatment with the 5-HT6 receptor antagonist, SB258585.
  
  
  CONCLUSIONS
  2FNQ1P was initially selected because of its suitable characteristics for 5-HT6 receptor probing in vitro in terms of affinity and specificity. Although in vivo imaging in rats cannot be considered as predictive of the clinical characteristics of the radiotracer, [(18)F]2FNQ1P appeared to be a suitable 5-HT6 PET tracer in feline and primate models. These preclinical results encourage us to pursue the clinical development of this first fluorinated 5-HT6 PET radiotracer.
authors.affiliation: Lyon Neuroscience Research Center, Université Claude Bernard Lyon 1; CNRS; INSERM, Lyon, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Becker
authors.forename: Julie
authors.initials: J
authors.lastname: Colomb
authors.forename: Véronique
authors.initials: V
authors.lastname: Sgambato-Faure
authors.forename: Léon
authors.initials: L
authors.lastname: Tremblay
authors.forename: Thierry
authors.initials: T
authors.lastname: Billard
authors.forename: Luc
authors.initials: L
authors.lastname: Zimmer
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging*; D002415:Cats; D004353:Drug Evaluation, Preclinical; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D005663:Furans / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D008252:Macaca fascicularis; D008297:Male; D009285:Naphthoquinones / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D010879:Piperazines / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000493:pharmacokinetics; D013449:Sulfonamides / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: C508754:2-acetylfuranonaphthoquinone; D005462:Fluorine Radioisotopes; D005663:Furans; D009285:Naphthoquinones; D010879:Piperazines; D019275:Radiopharmaceuticals; D011985:Receptors, Serotonin; C418570:SB 258585; D012702:Serotonin Antagonists; D013449:Sulfonamides; C097216:serotonin 6 receptor