title: PET imaging evaluation of [(18)F]DBT-10, a novel radioligand specific to α7 nicotinic acetylcholine receptors, in nonhuman primates.
abstract: OBJECTIVE
  Positron emission tomography (PET) radioligands specific to α7 nicotinic acetylcholine receptors (nAChRs) afford in vivo imaging of this receptor for neuropathologies such as Alzheimer's disease, schizophrenia, and substance abuse. This work aims to characterize the kinetic properties of an α7-nAChR-specific radioligand, 7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-[(18)F]-fluorodibenzo[b,d]thiophene 5,5-dioxide ([(18)F]DBT-10), in nonhuman primates.
  
  
  METHODS
  [(18)F]DBT-10 was produced via nucleophilic substitution of the nitro-precursor. Four Macaca mulatta subjects were imaged with [(18)F]DBT-10 PET, with measurement of [(18)F]DBT-10 parent concentrations and metabolism in arterial plasma. Baseline PET scans were acquired for all subjects. Following one scan, ex vivo analysis of brain tissue was performed to inspect for radiolabeled metabolites in brain. Three blocking scans with 0.69 and 1.24 mg/kg of the α7-nAChR-specific ligand ASEM were also acquired to assess dose-dependent blockade of [(18)F]DBT-10 binding. Kinetic analysis of PET data was performed using the metabolite-corrected input function to calculate the parent fraction corrected total distribution volume (V T/f P).
  
  
  RESULTS
  [(18)F]DBT-10 was produced within 90 min at high specific activities of 428 ± 436 GBq/μmol at end of synthesis. Metabolism of [(18)F]DBT-10 varied across subjects, stabilizing by 120 min post-injection at parent fractions of 15-55%. Uptake of [(18)F]DBT-10 in brain occurred rapidly, reaching peak standardized uptake values (SUVs) of 2.9-3.7 within 30 min. The plasma-free fraction was 18.8 ± 3.4%. No evidence for radiolabeled [(18)F]DBT-10 metabolites was found in ex vivo brain tissue samples. Kinetic analysis of PET data was best described by the two-tissue compartment model. Estimated V T/f P values were 193-376 ml/cm(3) across regions, with regional rank order of thalamus > frontal cortex > striatum > hippocampus > occipital cortex > cerebellum > pons. Dose-dependent blockade of [(18)F]DBT-10 binding by structural analog ASEM was observed throughout the brain, and occupancy plots yielded a V ND/f P estimate of 20 ± 16 ml/cm(3).
  
  
  CONCLUSIONS
  These results demonstrate suitable kinetic properties of [(18)F]DBT-10 for in vivo quantification of α7-nAChR binding in nonhuman primates.
authors.affiliation: PET Center, Yale University, 801 Howard Ave, PO Box 208048, New Haven, CT, 06520-8048, USA. ansel.hillmer@yale.edu.
authors.forename: Ansel T
authors.initials: AT
authors.lastname: Hillmer
authors.affiliation: PET Center, Yale University, 801 Howard Ave, PO Box 208048, New Haven, CT, 06520-8048, USA.
authors.forename: Ming-Qiang
authors.initials: MQ
authors.lastname: Zheng
authors.affiliation: PET Center, Yale University, 801 Howard Ave, PO Box 208048, New Haven, CT, 06520-8048, USA.
authors.forename: Songye
authors.initials: S
authors.lastname: Li
authors.affiliation: Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstraße 15, 04318, Leipzig, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Scheunemann
authors.affiliation: PET Center, Yale University, 801 Howard Ave, PO Box 208048, New Haven, CT, 06520-8048, USA.
authors.forename: Shu-fei
authors.initials: SF
authors.lastname: Lin
authors.affiliation: PET Center, Yale University, 801 Howard Ave, PO Box 208048, New Haven, CT, 06520-8048, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Holden
authors.affiliation: PET Center, Yale University, 801 Howard Ave, PO Box 208048, New Haven, CT, 06520-8048, USA.
authors.forename: David
authors.initials: D
authors.lastname: Labaree
authors.affiliation: PET Center, Yale University, 801 Howard Ave, PO Box 208048, New Haven, CT, 06520-8048, USA.
authors.forename: Jim
authors.initials: J
authors.lastname: Ropchan
authors.affiliation: Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstraße 15, 04318, Leipzig, Germany.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Teodoro
authors.affiliation: Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstraße 15, 04318, Leipzig, Germany.
authors.forename: Winnie
authors.initials: W
authors.lastname: Deuther-Conrad
authors.affiliation: PET Center, Yale University, 801 Howard Ave, PO Box 208048, New Haven, CT, 06520-8048, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Carson
authors.affiliation: Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstraße 15, 04318, Leipzig, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Brust
authors.affiliation: PET Center, Yale University, 801 Howard Ave, PO Box 208048, New Haven, CT, 06520-8048, USA.
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000818:Animals; D053961:Azabicyclo Compounds / Q000737:chemistry* / Q000493:pharmacokinetics; D001921:Brain / Q000000981:diagnostic imaging*; D002851:Chromatography, High Pressure Liquid; D003499:Cyclic S-Oxides / Q000737:chemistry* / Q000493:pharmacokinetics; D005260:Female; D005462:Fluorine Radioisotopes; D007700:Kinetics; D008253:Macaca mulatta; D008279:Magnetic Resonance Imaging; D008297:Male; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000737:chemistry* / Q000493:pharmacokinetics; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000737:chemistry*
chemical_list: D053961:Azabicyclo Compounds; D003499:Cyclic S-Oxides; C000611867:DBT-10; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D064569:alpha7 Nicotinic Acetylcholine Receptor
keywords: Alpha 7; Nicotine; Nicotinic acetylcholine receptor; PET