title: 11C-NS14492 as a novel PET radioligand for imaging cerebral alpha7 nicotinic acetylcholine receptors: in vivo evaluation and drug occupancy measurements.
abstract: Small-molecule α(7) nicotinic acetylcholine receptor (α(7)nAChR) agonists are currently validated for use as treatment for cognitive disturbances in schizophrenia and in Alzheimer disease. A suitable radiolabeled α(7)nAChR PET tracer would be important for in vivo quantification of α(7)nAChR binding in humans and to measure α(7)nAChR occupancy of α(7)nAChR drug candidates. Here, we present the radiosynthesis and in vivo evaluation of (11)C-NS14492 as a selective α(7)nAChR PET radioligand.
  
  
  METHODS
  The high-affinity α(7)nAChR-selective partial agonist NS14492 was radiolabeled by methylation of its desmethyl precursor using (11)C-methyl triflate. Female Danish Landrace pigs were studied at baseline and after intravenous administration of blocking doses of either the α(7)nAChR partial agonist SSR180711 or the unlabeled NS14492. (11)C-NS14492 was given as an intravenous bolus injection, and the pigs were scanned for 90 min both at baseline and in the blocked conditions. Arterial blood was collected during the scanning, plasma was counted, and parent compound fraction was determined with radio-high-performance liquid chromatography. PET data were quantified with a graphical analysis with arterial input; (11)C-NS14492 regional distribution volumes were calculated, and α(7)nAChR occupancy was determined using an occupancy plot.
  
  
  RESULTS
  (11)C-NS14492 had a high uptake in the pig brain, with the highest binding in the cerebral cortex and thalamus in accordance with α(7)nAChR distribution. Pretreatment with NS14492 and SSR180711 consistently decreased distribution volumes of (11)C-NS14492 in all examined regions, in a dose-dependent manner, supporting the finding that the radioligand binds selectively to α(7)nAChR in vivo.
  
  
  CONCLUSIONS
  We report here that (11)C-NS14492 is the first, to our knowledge, PET radioligand for α(7)nAChR showing a dose-dependent decline in cerebral binding after receptor blockade. This compound is considered a promising PET tracer for in vivo measurements of α(7)nAChR binding in the human brain.
authors.affiliation: Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Ettrup
authors.forename: Jens D
authors.initials: JD
authors.lastname: Mikkelsen
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Lehel
authors.forename: Jacob
authors.initials: J
authors.lastname: Madsen
authors.forename: Elsebet Ø
authors.initials: EØ
authors.lastname: Nielsen
authors.forename: Mikael
authors.initials: M
authors.lastname: Palner
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Timmermann
authors.forename: Dan
authors.initials: D
authors.lastname: Peters
authors.forename: Gitte M
authors.initials: GM
authors.lastname: Knudsen
mesh_terms: D000470:Alkaloids / Q000378:metabolism; D000818:Animals; D053961:Azabicyclo Compounds / Q000378:metabolism / Q000493:pharmacokinetics; D001392:Azocines / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002851:Chromatography, High Pressure Liquid; D004307:Dose-Response Relationship, Radiation; D005260:Female; D010069:Oxadiazoles / Q000378:metabolism / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D011807:Quinolizines / Q000378:metabolism; D019275:Radiopharmaceuticals / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013552:Swine; D014018:Tissue Distribution; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000093843:Quinolizidine Alkaloids
chemical_list: D000470:Alkaloids; D053961:Azabicyclo Compounds; D001392:Azocines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D010069:Oxadiazoles; D011807:Quinolizines; D019275:Radiopharmaceuticals; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C562073:4-(5-(1-methyl-1H-pyrrol-2-yl)-1,3,4-oxadiazol-2-yl)-1,4-diazabicyclo(3.2.2)nonane; C579167:Chrna7 protein, human; C579165:Chrna7 protein, rat; C516833:SSR180711; C004712:cytisine; D000093843:Quinolizidine Alkaloids