title: PET imaging of α7nicotinic acetylcholine receptors: a comparative study of [18F]ASEM and [18F]DBT-10 in nonhuman primates, and further evaluation of [18F]ASEM in humans.
abstract: OBJECTIVE
  The α7nicotinic acetylcholine receptor (nAChR) is implicated in many neuropsychiatric disorders, making it an important target for positron emission tomography (PET) imaging. The first aim of this work was to compare two α7nAChRs PET radioligands, [18F]ASEM (3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-6-([18F]fluorodibenzo[b,d]thiophene 5,5-dioxide) and [18F]DBT-10 (7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-([18F]fluorodibenzo[b,d]thiophene 5,5-dioxide), in nonhuman primates. The second aim was to assess further the quantification and test-retest variability of [18F]ASEM in humans.
  
  
  METHODS
  PET scans with high specific activity [18F]ASEM or [18F]DBT-10 were acquired in three rhesus monkeys (one male, two female), and the kinetic properties of these radiotracers were compared. Additional [18F]ASEM PET scans with blocking doses of nicotine, varenicline, and cold ASEM were acquired separately in two animals. Next, six human subjects (five male, one female) were imaged with [18F]ASEM PET for 180 min, and arterial sampling was used to measure the parent input function. Different modeling approaches were compared to identify the optimal analysis method and scan duration for quantification of [18F]ASEM distribution volume (VT). In addition, retest scans were acquired in four subjects (three male, one female), and the test-retest variability of VTwas assessed.
  
  
  RESULTS
  In the rhesus monkey brain [18F]ASEM and [18F]DBT-10 exhibited highly similar kinetic profiles. Dose-dependent blockade of [18F]ASEM binding was observed, while administration of either nicotine or varenicline did not change [18F]ASEM VT. [18F]ASEM was selected for further validation because it has been used in humans. Accurate quantification of [18F]ASEM VTin humans was achieved using multilinear analysis with at least 90 min of data acquisition, resulting in VTvalues ranging from 19.6 ± 2.5 mL/cm3in cerebellum to 25.9 ± 2.9 mL/cm3in thalamus. Test-retest variability of VTwas 11.7 ± 9.8%.
  
  
  CONCLUSIONS
  These results confirm [18F]ASEM as a suitable radiotracer for the imaging and quantification of α7nAChRs in humans.
authors.affiliation: PET Center, Yale University, PO Box 208048, 801 Howard Ave, 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, PO Box 208048, 801 Howard Ave, New Haven, CT, 06520-8048, USA.
authors.forename: Songye
authors.initials: S
authors.lastname: Li
authors.affiliation: PET Center, Yale University, PO Box 208048, 801 Howard Ave, New Haven, CT, 06520-8048, USA.
authors.forename: Ming-Qiang
authors.initials: MQ
authors.lastname: Zheng
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Permoserstraße 15, 04318, Leipzig, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Scheunemann
authors.affiliation: PET Center, Yale University, PO Box 208048, 801 Howard Ave, New Haven, CT, 06520-8048, USA.
authors.forename: Shu-Fei
authors.initials: SF
authors.lastname: Lin
authors.affiliation: PET Center, Yale University, PO Box 208048, 801 Howard Ave, New Haven, CT, 06520-8048, USA.
authors.forename: Nabeel
authors.initials: N
authors.lastname: Nabulsi
authors.affiliation: PET Center, Yale University, PO Box 208048, 801 Howard Ave, New Haven, CT, 06520-8048, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Holden
authors.affiliation: PET Center, Yale University, PO Box 208048, 801 Howard Ave, New Haven, CT, 06520-8048, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Pracitto
authors.affiliation: PET Center, Yale University, PO Box 208048, 801 Howard Ave, New Haven, CT, 06520-8048, USA.
authors.forename: David
authors.initials: D
authors.lastname: Labaree
authors.affiliation: PET Center, Yale University, PO Box 208048, 801 Howard Ave, New Haven, CT, 06520-8048, USA.
authors.forename: Jim
authors.initials: J
authors.lastname: Ropchan
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Permoserstraße 15, 04318, Leipzig, Germany.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Teodoro
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Permoserstraße 15, 04318, Leipzig, Germany.
authors.forename: Winnie
authors.initials: W
authors.lastname: Deuther-Conrad
authors.affiliation: PET Center, Yale University, PO Box 208048, 801 Howard Ave, New Haven, CT, 06520-8048, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Esterlis
authors.affiliation: PET Center, Yale University, PO Box 208048, 801 Howard Ave, New Haven, CT, 06520-8048, USA.
authors.forename: Kelly P
authors.initials: KP
authors.lastname: Cosgrove
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Permoserstraße 15, 04318, Leipzig, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Brust
authors.affiliation: PET Center, Yale University, PO Box 208048, 801 Howard Ave, New Haven, CT, 06520-8048, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Carson
authors.affiliation: PET Center, Yale University, PO Box 208048, 801 Howard Ave, New Haven, CT, 06520-8048, USA.
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000818:Animals; D053961:Azabicyclo Compounds; D003499:Cyclic S-Oxides; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007700:Kinetics; D008253:Macaca mulatta; D008297:Male; D049268:Positron-Emission Tomography / Q000379:methods*; D015203:Reproducibility of Results; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism*
chemical_list: C585155:3-(1,4-diazabicyclo(3.2.2)nonan-4-yl)-6-fluorodibenzo(b,d)thiophene 5,5-dioxide; D053961:Azabicyclo Compounds; D003499:Cyclic S-Oxides; C000611867:DBT-10; D064569:alpha7 Nicotinic Acetylcholine Receptor
keywords: ASEM; Alpha7; Nicotine; Nicotinic Acetylcholine Receptor; PET