Brain PET imaging of α7-nAChR with [18F]ASEM: Reproducibility, occupancy, receptor density, and changes in schizophrenia

Dean Foster Wong, Hiroto Kuwabara, Andrew Horti, Joshua M. Roberts, Ayon Nandi, Nicola Cascella, James R Brasic, Elise Weerts, Kelly Kitzmiller, Jenny A. Phan, Lorena Gapasin, Akira Sawa, Heather Valentine, Gary S Wand, Chakradhar Mishra, Noble George, Michael McDonald, Wojciech Lesniak, Daniel Holt, Babak Behnam AzadRobert F Dannals, William Kem, Robert Freedman, Albert Gjedde

Research output: Contribution to journalArticle

Abstract

Background: The α7 nicotinic acetylcholine receptor increasingly has been implicated in normal brain physiology, as well as in neuropsychiatric disorders. The highly cortical distribution of α7 nicotinic acetylcholine receptor suggests a role in cognition. Methods: We expanded the first-in-human PET imaging of α7 nicotinic acetylcholine receptor with [18F]ASEM from 5 to 21 healthy nonsmoking volunteers and added a feasibility study in 6 male patients with schizophrenia. Study aims included: (1) confirmation of test-retest reproducibility of [18F]ASEM binding, (2) demonstration of specificity by competition with DMXB-A, an α7 nicotinic acetylcholine receptor partial agonist, (3) estimation of [18F]ASEM binding potentials and α7 nicotinic acetylcholine receptor density in vivo in humans, and (4) demonstrating the feasibility of studying α7 nicotinic acetylcholine receptor as a target for schizophrenia. Results: Test-retest PET confirmed reproducibility (>90%) (variability ≤7%) of [18F]ASEM volume of distribution (VT) estimates in healthy volunteers. Repeated sessions of PET in 5 healthy subjects included baseline and effect of inhibition after oral administration of 150 mg DMXB-A. From reduction of binding potentials, we estimated the dose-dependent occupancy of α7 nicotinic acetylcholine receptor by DMXB-A at 17% to 49% for plasma concentrations at 60 to 200 nM DMXB-A. In agreement with evidence postmortem, α7 nicotinic acetylcholine receptor density averaged 0.67 to 0.82 nM and inhibitor affinity constant averaged 170 to 385 nM. Median VT in a feasibility study of 6 patients with schizophrenia was lower than in healthy volunteers in cingulate cortex, frontal cortex, and hippocampus (P = 0.02, corrected for multiple comparions, Mann-Whitney test). Conclusions: The current results confirm the reproducibility of [18F]ASEM VT estimates and the specificity of the tracer for α7 nicotinic acetylcholine receptor. Preliminary findings from our feasibility study of [18F]ASEM binding in patients with schizophrenia are suggestive and provide guidance for future studies with more subjects.

Original languageEnglish (US)
Pages (from-to)656-667
Number of pages12
JournalInternational Journal of Neuropsychopharmacology
Volume21
Issue number7
DOIs
StatePublished - Jan 1 2018

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Nicotinic Receptors
Neuroimaging
Schizophrenia
Healthy Volunteers
Feasibility Studies
3-(1,4-diazabicyclo(3.2.2)nonan-4-yl)-6-fluorodibenzo(b,d)thiophene 5,5-dioxide
Gyrus Cinguli
Frontal Lobe
Reproducibility of Results
Cognition
Oral Administration
Hippocampus
Brain

Keywords

  • Nicotinic acetylcholine receptors
  • PET imaging
  • Schizophrenia

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health
  • Pharmacology (medical)

Cite this

Brain PET imaging of α7-nAChR with [18F]ASEM : Reproducibility, occupancy, receptor density, and changes in schizophrenia. / Wong, Dean Foster; Kuwabara, Hiroto; Horti, Andrew; Roberts, Joshua M.; Nandi, Ayon; Cascella, Nicola; Brasic, James R; Weerts, Elise; Kitzmiller, Kelly; Phan, Jenny A.; Gapasin, Lorena; Sawa, Akira; Valentine, Heather; Wand, Gary S; Mishra, Chakradhar; George, Noble; McDonald, Michael; Lesniak, Wojciech; Holt, Daniel; Behnam Azad, Babak; Dannals, Robert F; Kem, William; Freedman, Robert; Gjedde, Albert.

In: International Journal of Neuropsychopharmacology, Vol. 21, No. 7, 01.01.2018, p. 656-667.

Research output: Contribution to journalArticle

Wong, Dean Foster ; Kuwabara, Hiroto ; Horti, Andrew ; Roberts, Joshua M. ; Nandi, Ayon ; Cascella, Nicola ; Brasic, James R ; Weerts, Elise ; Kitzmiller, Kelly ; Phan, Jenny A. ; Gapasin, Lorena ; Sawa, Akira ; Valentine, Heather ; Wand, Gary S ; Mishra, Chakradhar ; George, Noble ; McDonald, Michael ; Lesniak, Wojciech ; Holt, Daniel ; Behnam Azad, Babak ; Dannals, Robert F ; Kem, William ; Freedman, Robert ; Gjedde, Albert. / Brain PET imaging of α7-nAChR with [18F]ASEM : Reproducibility, occupancy, receptor density, and changes in schizophrenia. In: International Journal of Neuropsychopharmacology. 2018 ; Vol. 21, No. 7. pp. 656-667.
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abstract = "Background: The α7 nicotinic acetylcholine receptor increasingly has been implicated in normal brain physiology, as well as in neuropsychiatric disorders. The highly cortical distribution of α7 nicotinic acetylcholine receptor suggests a role in cognition. Methods: We expanded the first-in-human PET imaging of α7 nicotinic acetylcholine receptor with [18F]ASEM from 5 to 21 healthy nonsmoking volunteers and added a feasibility study in 6 male patients with schizophrenia. Study aims included: (1) confirmation of test-retest reproducibility of [18F]ASEM binding, (2) demonstration of specificity by competition with DMXB-A, an α7 nicotinic acetylcholine receptor partial agonist, (3) estimation of [18F]ASEM binding potentials and α7 nicotinic acetylcholine receptor density in vivo in humans, and (4) demonstrating the feasibility of studying α7 nicotinic acetylcholine receptor as a target for schizophrenia. Results: Test-retest PET confirmed reproducibility (>90{\%}) (variability ≤7{\%}) of [18F]ASEM volume of distribution (VT) estimates in healthy volunteers. Repeated sessions of PET in 5 healthy subjects included baseline and effect of inhibition after oral administration of 150 mg DMXB-A. From reduction of binding potentials, we estimated the dose-dependent occupancy of α7 nicotinic acetylcholine receptor by DMXB-A at 17{\%} to 49{\%} for plasma concentrations at 60 to 200 nM DMXB-A. In agreement with evidence postmortem, α7 nicotinic acetylcholine receptor density averaged 0.67 to 0.82 nM and inhibitor affinity constant averaged 170 to 385 nM. Median VT in a feasibility study of 6 patients with schizophrenia was lower than in healthy volunteers in cingulate cortex, frontal cortex, and hippocampus (P = 0.02, corrected for multiple comparions, Mann-Whitney test). Conclusions: The current results confirm the reproducibility of [18F]ASEM VT estimates and the specificity of the tracer for α7 nicotinic acetylcholine receptor. Preliminary findings from our feasibility study of [18F]ASEM binding in patients with schizophrenia are suggestive and provide guidance for future studies with more subjects.",
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T1 - Brain PET imaging of α7-nAChR with [18F]ASEM

T2 - Reproducibility, occupancy, receptor density, and changes in schizophrenia

AU - Wong, Dean Foster

AU - Kuwabara, Hiroto

AU - Horti, Andrew

AU - Roberts, Joshua M.

AU - Nandi, Ayon

AU - Cascella, Nicola

AU - Brasic, James R

AU - Weerts, Elise

AU - Kitzmiller, Kelly

AU - Phan, Jenny A.

AU - Gapasin, Lorena

AU - Sawa, Akira

AU - Valentine, Heather

AU - Wand, Gary S

AU - Mishra, Chakradhar

AU - George, Noble

AU - McDonald, Michael

AU - Lesniak, Wojciech

AU - Holt, Daniel

AU - Behnam Azad, Babak

AU - Dannals, Robert F

AU - Kem, William

AU - Freedman, Robert

AU - Gjedde, Albert

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Background: The α7 nicotinic acetylcholine receptor increasingly has been implicated in normal brain physiology, as well as in neuropsychiatric disorders. The highly cortical distribution of α7 nicotinic acetylcholine receptor suggests a role in cognition. Methods: We expanded the first-in-human PET imaging of α7 nicotinic acetylcholine receptor with [18F]ASEM from 5 to 21 healthy nonsmoking volunteers and added a feasibility study in 6 male patients with schizophrenia. Study aims included: (1) confirmation of test-retest reproducibility of [18F]ASEM binding, (2) demonstration of specificity by competition with DMXB-A, an α7 nicotinic acetylcholine receptor partial agonist, (3) estimation of [18F]ASEM binding potentials and α7 nicotinic acetylcholine receptor density in vivo in humans, and (4) demonstrating the feasibility of studying α7 nicotinic acetylcholine receptor as a target for schizophrenia. Results: Test-retest PET confirmed reproducibility (>90%) (variability ≤7%) of [18F]ASEM volume of distribution (VT) estimates in healthy volunteers. Repeated sessions of PET in 5 healthy subjects included baseline and effect of inhibition after oral administration of 150 mg DMXB-A. From reduction of binding potentials, we estimated the dose-dependent occupancy of α7 nicotinic acetylcholine receptor by DMXB-A at 17% to 49% for plasma concentrations at 60 to 200 nM DMXB-A. In agreement with evidence postmortem, α7 nicotinic acetylcholine receptor density averaged 0.67 to 0.82 nM and inhibitor affinity constant averaged 170 to 385 nM. Median VT in a feasibility study of 6 patients with schizophrenia was lower than in healthy volunteers in cingulate cortex, frontal cortex, and hippocampus (P = 0.02, corrected for multiple comparions, Mann-Whitney test). Conclusions: The current results confirm the reproducibility of [18F]ASEM VT estimates and the specificity of the tracer for α7 nicotinic acetylcholine receptor. Preliminary findings from our feasibility study of [18F]ASEM binding in patients with schizophrenia are suggestive and provide guidance for future studies with more subjects.

AB - Background: The α7 nicotinic acetylcholine receptor increasingly has been implicated in normal brain physiology, as well as in neuropsychiatric disorders. The highly cortical distribution of α7 nicotinic acetylcholine receptor suggests a role in cognition. Methods: We expanded the first-in-human PET imaging of α7 nicotinic acetylcholine receptor with [18F]ASEM from 5 to 21 healthy nonsmoking volunteers and added a feasibility study in 6 male patients with schizophrenia. Study aims included: (1) confirmation of test-retest reproducibility of [18F]ASEM binding, (2) demonstration of specificity by competition with DMXB-A, an α7 nicotinic acetylcholine receptor partial agonist, (3) estimation of [18F]ASEM binding potentials and α7 nicotinic acetylcholine receptor density in vivo in humans, and (4) demonstrating the feasibility of studying α7 nicotinic acetylcholine receptor as a target for schizophrenia. Results: Test-retest PET confirmed reproducibility (>90%) (variability ≤7%) of [18F]ASEM volume of distribution (VT) estimates in healthy volunteers. Repeated sessions of PET in 5 healthy subjects included baseline and effect of inhibition after oral administration of 150 mg DMXB-A. From reduction of binding potentials, we estimated the dose-dependent occupancy of α7 nicotinic acetylcholine receptor by DMXB-A at 17% to 49% for plasma concentrations at 60 to 200 nM DMXB-A. In agreement with evidence postmortem, α7 nicotinic acetylcholine receptor density averaged 0.67 to 0.82 nM and inhibitor affinity constant averaged 170 to 385 nM. Median VT in a feasibility study of 6 patients with schizophrenia was lower than in healthy volunteers in cingulate cortex, frontal cortex, and hippocampus (P = 0.02, corrected for multiple comparions, Mann-Whitney test). Conclusions: The current results confirm the reproducibility of [18F]ASEM VT estimates and the specificity of the tracer for α7 nicotinic acetylcholine receptor. Preliminary findings from our feasibility study of [18F]ASEM binding in patients with schizophrenia are suggestive and provide guidance for future studies with more subjects.

KW - Nicotinic acetylcholine receptors

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