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 language | English (US) |
|---|---|
| Pages (from-to) | 2863-2872 |
| Number of pages | 10 |
| Journal | Psychopharmacology |
| Volume | 232 |
| Issue number | 15 |
| DOIs | |
| State | Published - Apr 7 2015 |
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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 journal › Article
}
TY - JOUR
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
Y1 - 2015/4/7
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.
KW - Antidepressant
KW - Antipsychotic
KW - Brain imaging
KW - Dopamine receptor
KW - Human
KW - Neuroimaging
KW - PET
KW - Serotonin receptor
UR - http://www.scopus.com/inward/record.url?scp=84937735558&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84937735558&partnerID=8YFLogxK
U2 - 10.1007/s00213-015-3922-1
DO - 10.1007/s00213-015-3922-1
M3 - Article
C2 - 25843749
AN - SCOPUS:84937735558
VL - 232
SP - 2863
EP - 2872
JO - Psychopharmacology
JF - Psychopharmacology
SN - 0033-3158
IS - 15
ER -