title: Synthesis and pharmacological evaluation of a new series of radiolabeled ligands for 5-HT7 receptor PET neuroimaging.
abstract: BACKGROUND
  The brain serotonin-7 receptor (5-HT7) is the most recently discovered serotonin receptor. It is targeted by several drug-candidates in psychopharmacology and neuropharmacology. In these fields, positron emission tomography (PET) is a molecular imaging modality offering great promise for accelerating the development process from preclinical discovery to clinical phases. We recently described fluorinated 5-HT7 radioligands, inspired by the structure of SB269970, the prototypical 5-HT7 antagonist. Although these results were promising, it appeared that the radiotracer-candidates suffered, among other drawbacks, from too low a 5-HT7 receptor affinity.
  
  
  METHODS
  In the present study, seven structural analogs of SB269970 were synthesized using design strategies aiming to improve their radiopharmacological properties. Their 5-HT7 binding properties were investigated by cellular functional assay. The nitro-precursors of the analogs were radiolabeled by [(18)F-]nucleophilic substitution, and in vitro autoradiography was performed in rat brain, followed by in vivo microPET.
  
  
  RESULTS
  The chemical and radiochemical purity of the fluorine radiotracers was>99% with specific activity in the 40-129GBq/μmol range. The seven derivatives presented heterogeneous binding affinities toward 5-HT7 and 5-HT1A receptors. While [(18)F]2F3P3 had promising characteristics in vitro, it showed poor brain penetration in vivo, partially reversed after pharmacological inhibition of P-glycoprotein.
  
  
  CONCLUSIONS
  These results indicated that, while chemical modification of these series improved several radiotracer-candidates in terms of 5-HT7 receptor affinity and specificity toward 5-HT1A receptors, other physicochemical modulations would be required in order to increase brain penetration.
authors.affiliation: University Lyon 1, CNRS, Institute of Chemistry and Biochemistry (UMR 5246), Villeurbanne, France; CERMEP-Imagerie du Vivant, Lyon, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Colomb
authors.affiliation: University Lyon 1, CNRS, INSERM, Lyon Neuroscience Research Center (UMR 5292, U 1028), Lyon, France; CERMEP-Imagerie du Vivant, Lyon, France; Hospices Civils de Lyon, Lyon, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Becker
authors.affiliation: University Lyon 1, CNRS, Institute of Chemistry and Biochemistry (UMR 5246), Villeurbanne, France.
authors.forename: Elsa
authors.initials: E
authors.lastname: Forcellini
authors.affiliation: University Lyon 1, CNRS, Institute of Chemistry and Biochemistry (UMR 5246), Villeurbanne, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Meyer
authors.affiliation: University Lyon 1, CNRS, Institute of Chemistry and Biochemistry (UMR 5246), Villeurbanne, France.
authors.forename: Lauriane
authors.initials: L
authors.lastname: Buisson
authors.affiliation: University Lyon 1, CNRS, INSERM, Lyon Neuroscience Research Center (UMR 5292, U 1028), Lyon, France; CERMEP-Imagerie du Vivant, Lyon, France; Hospices Civils de Lyon, Lyon, France. Electronic address: zimmer@univ-lyon1.fr.
authors.forename: Luc
authors.initials: L
authors.lastname: Zimmer
authors.affiliation: University Lyon 1, CNRS, Institute of Chemistry and Biochemistry (UMR 5246), Villeurbanne, France; CERMEP-Imagerie du Vivant, Lyon, France. Electronic address: billard@univ-lyon1.fr.
authors.forename: Thierry
authors.initials: T
authors.lastname: Billard
mesh_terms: D000818:Animals; D016466:CHO Cells; D060326:Chemistry Techniques, Synthetic; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008297:Male; D059906:Neuroimaging / Q000379:methods*; D010636:Phenols / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods*; D011854:Radiochemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism*; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism
chemical_list: D008024:Ligands; D010636:Phenols; D011985:Receptors, Serotonin; C404922:SB 269970; D013449:Sulfonamides; C104425:serotonin 7 receptor
keywords: 5-HT(7); Fluorine-18; PET; Positron emission tomography; Serotonin