title: ITI-007 demonstrates brain occupancy at serotonin 5-HT₂A and dopamine D₂ receptors and serotonin transporters using positron emission tomography in healthy volunteers.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Intra-Cellular Therapies, Inc. (ITI), 3960 Broadway, 6th floor, New York, NY, 10032, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Davis
authors.forename: Kimberly E
authors.initials: KE
authors.lastname: Vanover
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhou
authors.forename: James R
authors.initials: JR
authors.lastname: Brašić
authors.forename: Maria
authors.initials: M
authors.lastname: Guevara
authors.forename: Blanca
authors.initials: B
authors.lastname: Bisuna
authors.forename: Weiguo
authors.initials: W
authors.lastname: Ye
authors.forename: Vanessa
authors.initials: V
authors.lastname: Raymont
authors.forename: William
authors.initials: W
authors.lastname: Willis
authors.forename: Anil
authors.initials: A
authors.lastname: Kumar
authors.forename: Lorena
authors.initials: L
authors.lastname: Gapasin
authors.forename: D Ronald
authors.initials: DR
authors.lastname: Goldwater
authors.forename: Sharon
authors.initials: S
authors.lastname: Mates
authors.forename: Dean F
authors.initials: DF
authors.lastname: Wong
mesh_terms: D000293:Adolescent; D000328:Adult; D014150:Antipsychotic Agents / Q000494:pharmacology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D044402:Receptor, Serotonin, 5-HT2A; D017448:Receptors, Dopamine D2; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin
references.citation: Mol Psychiatry. 2008 Jun;13(6):606-13, 557
references.pmid: 18268503
references.citation: Nucl Med Biol. 2002 Jul;29(5):509-15
references.pmid: 12088720
references.citation: Am J Psychiatry. 1997 Sep;154(9):1209-13
references.pmid: 9286178
references.citation: J Psychiatr Res. 2012 Aug;46(8):1029-35
references.pmid: 22575330
references.citation: Am J Psychiatry. 1995 Oct;152(10 ):1444-9
references.pmid: 7573582
references.citation: J Med Chem. 2003 Jun 19;46(13):2740-54
references.pmid: 12801237
references.citation: Nat Sci Sleep. 2010 Jul 28;2:139-50
references.pmid: 23616706
references.citation: J Psychopharmacol. 2008 Mar;22(2 Suppl):46-55
references.pmid: 18477620
references.citation: J Nucl Med. 2006 Feb;47(2):313-9
references.pmid: 16455638
references.citation: Am J Psychiatry. 2004 May;161(5):826-35
references.pmid: 15121647
references.citation: Am J Psychiatry. 2006 Sep;163(9):1580-7
references.pmid: 16946184
references.citation: Curr Opin Investig Drugs. 2001 Jan;2(1):123-32
references.pmid: 11527004
references.citation: Synapse. 2003 Dec 1;50(3):251-60
references.pmid: 14515343
references.citation: Neuropsychopharmacology. 2006 Sep;31(9):1991-2001
references.pmid: 16738543
references.citation: Arch Gen Psychiatry. 1992 Jul;49(7):538-44
references.pmid: 1352677
references.citation: Neuropsychopharmacology. 2005 Dec;30(12 ):2283-9
references.pmid: 16123775
references.citation: Pharmacol Ther. 2007 Feb;113(2):296-320
references.pmid: 17049611
references.citation: J Med Chem. 2014 Mar 27;57(6):2670-82
references.pmid: 24559051
references.citation: Psychopharmacology (Berl). 2000 Jul;150(4):422-9
references.pmid: 10958084
references.citation: Schizophr Bull. 2012 Jan;38(1):167-77
references.pmid: 20513652
references.citation: Biol Psychiatry. 2010 Jun 15;67(12 ):1154-62
references.pmid: 20434136
references.citation: J Cereb Blood Flow Metab. 2007 Jan;27(1):161-72
references.pmid: 16685260
references.citation: Neuropsychopharmacology. 2005 Dec;30(12 ):2205-15
references.pmid: 15886717
references.citation: J Psychiatry Neurosci. 2008 Nov;33(6):499-508
references.pmid: 18982172
references.citation: Neuroimage. 2010 Feb 15;49(4):2947-57
references.pmid: 19931403
references.citation: Eur J Pharmacol. 2000 Oct 27;407(1-2):39-46
references.pmid: 11050288
references.citation: Psychopharmacology (Berl). 2013 Sep;229(2):245-52
references.pmid: 23649882
references.citation: Eur J Nucl Med Mol Imaging. 2005 Aug;32(8):952-8
references.pmid: 15841376
references.citation: Neuropsychopharmacology. 2006 May;31(5):1027-35
references.pmid: 16237387
references.citation: Neuropsychopharmacology. 2002 Aug;27(2):248-59
references.pmid: 12093598
references.citation: Arch Gen Psychiatry. 2003 Oct;60(10 ):974-7
references.pmid: 14557141
references.citation: J Clin Psychiatry. 2010 Apr;71(4):451-62
references.pmid: 20361905
references.citation: Am J Psychiatry. 2008 Mar;165(3):398; author reply 398-9
references.pmid: 18316435
references.citation: Biol Psychiatry. 1993 Feb 15;33(4):227-35
references.pmid: 8097114
references.citation: Am J Psychiatry. 2000 Apr;157(4):514-20
references.pmid: 10739409
references.citation: Eur Neuropsychopharmacol. 1996 Nov;6(4):305-10
references.pmid: 8985714
references.citation: Drugs. 1986 Dec;32(6):481-508
references.pmid: 2878798
references.citation: Clin Neuropharmacol. 1997 Jun;20(3):210-4
references.pmid: 9197943
references.citation: Nucl Med Biol. 2000 Aug;27(6):627-30
references.pmid: 11056380
references.citation: J Clin Psychopharmacol. 1995 Feb;15(1 Suppl 1):19S-23S
references.pmid: 7537284
references.citation: J Pharmacol Exp Ther. 2007 Aug;322(2):862-70
references.pmid: 17519387
references.citation: Psychopharmacology (Berl). 2008 Oct;200(3):439-50
references.pmid: 18661256
references.citation: Nat Rev Drug Discov. 2004 Apr;3(4):353-9
references.pmid: 15060530
references.citation: Eur J Neurol. 2007 May;14 (5):523-8
references.pmid: 17437611
references.citation: Arch Gen Psychiatry. 2004 Dec;61(12 ):1271-9
references.pmid: 15583118
references.citation: Biol Psychiatry. 2005 Jun 15;57(12 ):1510-6
references.pmid: 15953487
references.citation: Neuropsychopharmacology. 2003 Feb;28(2):402-12
references.pmid: 12589395
references.citation: Int J Neuropsychopharmacol. 2010 Aug;13(7):951-60
references.pmid: 20392299
references.citation: Drugs. 1986 Oct;32(4):313-34
references.pmid: 3096686
references.citation: J Psychiatry Neurosci. 2007 Mar;32(2):86-102
references.pmid: 17353938
references.citation: Neuroimage. 2003 Apr;18(4):975-89
references.pmid: 12725772
references.citation: Am J Psychiatry. 2007 Sep;164(9):1411-7
references.pmid: 17728427
references.citation: Pharmacol Biochem Behav. 2001 Mar;68(3):363-70
references.pmid: 11325387
references.citation: Am J Psychiatry. 1999 Jun;156(6):869-75
references.pmid: 10360125
references.citation: Psychopharmacology (Berl). 2015 Feb;232(3):605-21
references.pmid: 25120104
references.citation: Am J Psychiatry. 1976 Feb;133(2):197-202
references.pmid: 1251927