Abstract | RATIONALE: OBJECTIVES: 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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Authors | Robert E Davis, Kimberly E Vanover, Yun Zhou, James R Brašić, Maria Guevara, Blanca Bisuna, Weiguo Ye, Vanessa Raymont, William Willis, Anil Kumar, Lorena Gapasin, D Ronald Goldwater, Sharon Mates, Dean F Wong |
Journal | Psychopharmacology
(Psychopharmacology (Berl))
Vol. 232
Issue 15
Pg. 2863-72
(Aug 2015)
ISSN: 1432-2072 [Electronic] Germany |
PMID | 25843749
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antipsychotic Agents
- Receptor, Serotonin, 5-HT2A
- Receptors, Dopamine D2
- Serotonin Plasma Membrane Transport Proteins
- Serotonin
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Topics |
- Adolescent
- Adult
- Antipsychotic Agents
(pharmacology)
- Brain
(drug effects, metabolism)
- Healthy Volunteers
- Humans
- Male
- Middle Aged
- Positron-Emission Tomography
- Receptor, Serotonin, 5-HT2A
(metabolism)
- Receptors, Dopamine D2
(metabolism)
- Schizophrenia
(drug therapy)
- Serotonin
(metabolism)
- Serotonin Plasma Membrane Transport Proteins
(metabolism)
- Young Adult
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