ITI-007 demonstrates brain occupancy at serotonin 5-HT2A and dopamine D2 receptors and serotonin transporters using positron emission tomography in healthy volunteers

Robert E. Davis, Kimberly E. Vanover, Yun Zhou, James R Brasic, Maria Guevara, Blanca Bisuna, Weiguo Ye, Vanessa Raymont, William Willis, Anil Kumar, Lorena Gapasin, D. Ronald Goldwater, Sharon Mates, Dean Foster Wong

Research output: Contribution to journalArticle

Abstract

Rationale: Central modulation of serotonin and dopamine underlies efficacy for a variety of psychiatric therapeutics. ITI-007 is an investigational new drug in development for treatment of schizophrenia, mood disorders, and other neuropsychiatric disorders. Objectives: The purpose of this study was to determine brain occupancy of ITI-007 at serotonin 5-HT2A receptors, dopamine D2 receptors, and serotonin transporters using positron emission tomography (PET) in 16 healthy volunteers. Methods: Carbon-11-MDL100907, carbon-11-raclopride, and carbon-11-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile) (carbon-11-DASB) were used as the radiotracers for imaging 5-HT2A receptors, D2 receptors, and serotonin transporters, respectively. Brain regions of interest were outlined using magnetic resonance tomography (MRT) with cerebellum as the reference region. Binding potentials were estimated by fitting a simplified reference tissue model to the measured tissue-time activity curves. Target occupancy was expressed as percent change in the binding potentials before and after ITI-007 administration. Results: Oral ITI-007 (10-40 mg) was safe and well tolerated. ITI-007 rapidly entered the brain with long-lasting and dose-related occupancy. ITI-007 (10 mg) demonstrated high occupancy (>80 %) of cortical 5-HT2A receptors and low occupancy of striatal D2 receptors (~12 %). D2 receptor occupancy increased with dose and significantly correlated with plasma concentrations (r 2∈=∈0.68, p∈=∈0.002). ITI-007 (40 mg) resulted in peak occupancy up to 39 % of striatal D2 receptors and 33 % of striatal serotonin transporters. Conclusions: The results provide evidence for a central mechanism of action via dopaminergic and serotonergic pathways for ITI-007 in living human brain and valuable information to aid dose selection for future clinical trials.

Original languageEnglish (US)
Pages (from-to)2863-2872
Number of pages10
JournalPsychopharmacology
Volume232
Issue number15
DOIs
StatePublished - Apr 7 2015

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Serotonin Plasma Membrane Transport Proteins
Dopamine D2 Receptors
Corpus Striatum
Receptor, Serotonin, 5-HT2A
Positron-Emission Tomography
Serotonin
Healthy Volunteers
Carbon
Brain
Investigational Drugs
Raclopride
Mood Disorders
Cerebellum
Psychiatry
Dopamine
Schizophrenia
Magnetic Resonance Spectroscopy
Tomography
Clinical Trials
Therapeutics

Keywords

  • Antidepressant
  • Antipsychotic
  • Brain imaging
  • Dopamine receptor
  • Human
  • Neuroimaging
  • PET
  • Serotonin receptor

ASJC Scopus subject areas

  • Pharmacology

Cite this

ITI-007 demonstrates brain occupancy at serotonin 5-HT2A and dopamine D2 receptors and serotonin transporters using positron emission tomography in healthy volunteers. / Davis, Robert E.; Vanover, Kimberly E.; Zhou, Yun; Brasic, James R; Guevara, Maria; Bisuna, Blanca; Ye, Weiguo; Raymont, Vanessa; Willis, William; Kumar, Anil; Gapasin, Lorena; Goldwater, D. Ronald; Mates, Sharon; Wong, Dean Foster.

In: Psychopharmacology, Vol. 232, No. 15, 07.04.2015, p. 2863-2872.

Research output: Contribution to journalArticle

Davis, RE, Vanover, KE, Zhou, Y, Brasic, JR, Guevara, M, Bisuna, B, Ye, W, Raymont, V, Willis, W, Kumar, A, Gapasin, L, Goldwater, DR, Mates, S & Wong, DF 2015, 'ITI-007 demonstrates brain occupancy at serotonin 5-HT2A and dopamine D2 receptors and serotonin transporters using positron emission tomography in healthy volunteers', Psychopharmacology, vol. 232, no. 15, pp. 2863-2872. https://doi.org/10.1007/s00213-015-3922-1
Davis, Robert E. ; Vanover, Kimberly E. ; Zhou, Yun ; Brasic, James R ; Guevara, Maria ; Bisuna, Blanca ; Ye, Weiguo ; Raymont, Vanessa ; Willis, William ; Kumar, Anil ; Gapasin, Lorena ; Goldwater, D. Ronald ; Mates, Sharon ; Wong, Dean Foster. / ITI-007 demonstrates brain occupancy at serotonin 5-HT2A and dopamine D2 receptors and serotonin transporters using positron emission tomography in healthy volunteers. In: Psychopharmacology. 2015 ; Vol. 232, No. 15. pp. 2863-2872.
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abstract = "Rationale: Central modulation of serotonin and dopamine underlies efficacy for a variety of psychiatric therapeutics. ITI-007 is an investigational new drug in development for treatment of schizophrenia, mood disorders, and other neuropsychiatric disorders. Objectives: The purpose of this study was to determine brain occupancy of ITI-007 at serotonin 5-HT2A receptors, dopamine D2 receptors, and serotonin transporters using positron emission tomography (PET) in 16 healthy volunteers. Methods: Carbon-11-MDL100907, carbon-11-raclopride, and carbon-11-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile) (carbon-11-DASB) were used as the radiotracers for imaging 5-HT2A receptors, D2 receptors, and serotonin transporters, respectively. Brain regions of interest were outlined using magnetic resonance tomography (MRT) with cerebellum as the reference region. Binding potentials were estimated by fitting a simplified reference tissue model to the measured tissue-time activity curves. Target occupancy was expressed as percent change in the binding potentials before and after ITI-007 administration. Results: Oral ITI-007 (10-40 mg) was safe and well tolerated. ITI-007 rapidly entered the brain with long-lasting and dose-related occupancy. ITI-007 (10 mg) demonstrated high occupancy (>80 {\%}) of cortical 5-HT2A receptors and low occupancy of striatal D2 receptors (~12 {\%}). D2 receptor occupancy increased with dose and significantly correlated with plasma concentrations (r 2∈=∈0.68, p∈=∈0.002). ITI-007 (40 mg) resulted in peak occupancy up to 39 {\%} of striatal D2 receptors and 33 {\%} of striatal serotonin transporters. Conclusions: The results provide evidence for a central mechanism of action via dopaminergic and serotonergic pathways for ITI-007 in living human brain and valuable information to aid dose selection for future clinical trials.",
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T1 - ITI-007 demonstrates brain occupancy at serotonin 5-HT2A and dopamine D2 receptors and serotonin transporters using positron emission tomography in healthy volunteers

AU - Davis, Robert E.

AU - Vanover, Kimberly E.

AU - Zhou, Yun

AU - Brasic, James R

AU - Guevara, Maria

AU - Bisuna, Blanca

AU - Ye, Weiguo

AU - Raymont, Vanessa

AU - Willis, William

AU - Kumar, Anil

AU - Gapasin, Lorena

AU - Goldwater, D. Ronald

AU - Mates, Sharon

AU - Wong, Dean Foster

PY - 2015/4/7

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N2 - Rationale: Central modulation of serotonin and dopamine underlies efficacy for a variety of psychiatric therapeutics. ITI-007 is an investigational new drug in development for treatment of schizophrenia, mood disorders, and other neuropsychiatric disorders. Objectives: The purpose of this study was to determine brain occupancy of ITI-007 at serotonin 5-HT2A receptors, dopamine D2 receptors, and serotonin transporters using positron emission tomography (PET) in 16 healthy volunteers. Methods: Carbon-11-MDL100907, carbon-11-raclopride, and carbon-11-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile) (carbon-11-DASB) were used as the radiotracers for imaging 5-HT2A receptors, D2 receptors, and serotonin transporters, respectively. Brain regions of interest were outlined using magnetic resonance tomography (MRT) with cerebellum as the reference region. Binding potentials were estimated by fitting a simplified reference tissue model to the measured tissue-time activity curves. Target occupancy was expressed as percent change in the binding potentials before and after ITI-007 administration. Results: Oral ITI-007 (10-40 mg) was safe and well tolerated. ITI-007 rapidly entered the brain with long-lasting and dose-related occupancy. ITI-007 (10 mg) demonstrated high occupancy (>80 %) of cortical 5-HT2A receptors and low occupancy of striatal D2 receptors (~12 %). D2 receptor occupancy increased with dose and significantly correlated with plasma concentrations (r 2∈=∈0.68, p∈=∈0.002). ITI-007 (40 mg) resulted in peak occupancy up to 39 % of striatal D2 receptors and 33 % of striatal serotonin transporters. Conclusions: The results provide evidence for a central mechanism of action via dopaminergic and serotonergic pathways for ITI-007 in living human brain and valuable information to aid dose selection for future clinical trials.

AB - Rationale: Central modulation of serotonin and dopamine underlies efficacy for a variety of psychiatric therapeutics. ITI-007 is an investigational new drug in development for treatment of schizophrenia, mood disorders, and other neuropsychiatric disorders. Objectives: The purpose of this study was to determine brain occupancy of ITI-007 at serotonin 5-HT2A receptors, dopamine D2 receptors, and serotonin transporters using positron emission tomography (PET) in 16 healthy volunteers. Methods: Carbon-11-MDL100907, carbon-11-raclopride, and carbon-11-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile) (carbon-11-DASB) were used as the radiotracers for imaging 5-HT2A receptors, D2 receptors, and serotonin transporters, respectively. Brain regions of interest were outlined using magnetic resonance tomography (MRT) with cerebellum as the reference region. Binding potentials were estimated by fitting a simplified reference tissue model to the measured tissue-time activity curves. Target occupancy was expressed as percent change in the binding potentials before and after ITI-007 administration. Results: Oral ITI-007 (10-40 mg) was safe and well tolerated. ITI-007 rapidly entered the brain with long-lasting and dose-related occupancy. ITI-007 (10 mg) demonstrated high occupancy (>80 %) of cortical 5-HT2A receptors and low occupancy of striatal D2 receptors (~12 %). D2 receptor occupancy increased with dose and significantly correlated with plasma concentrations (r 2∈=∈0.68, p∈=∈0.002). ITI-007 (40 mg) resulted in peak occupancy up to 39 % of striatal D2 receptors and 33 % of striatal serotonin transporters. Conclusions: The results provide evidence for a central mechanism of action via dopaminergic and serotonergic pathways for ITI-007 in living human brain and valuable information to aid dose selection for future clinical trials.

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KW - Antipsychotic

KW - Brain imaging

KW - Dopamine receptor

KW - Human

KW - Neuroimaging

KW - PET

KW - Serotonin receptor

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