Skip to main content
SpringerLink
Log in

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

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Aizenberg D, Gur S, Zemishlany Z, Granek M, Jeczmien P, Weizman A (1997) Mianserin, a 5-HT2a/2c and alpha 2 antagonist, in the treatment of sexual dysfunction induced by serotonin reuptake inhibitors. Clin Neuropharmacol 20(3):210–214

    Article  CAS  PubMed  Google Scholar 

  • Alex KD, Pehek EA (2007) Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission. Pharmacol Ther 113(2):296–320

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Benfield P, Ward A (1986) Fluvoxamine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness. Drugs 32(4):313–334

    Article  CAS  PubMed  Google Scholar 

  • Benfield P, Heel RC, Lewis SP (1986) Fluoxetine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness. Drugs 32(6):481–508

    Article  CAS  PubMed  Google Scholar 

  • Bhagwagar Z, Hinz R, Taylor M, Fancy S, Cowen P, Grasby P (2006) Increased 5-HT(2A) receptor binding in euthymic, medication-free patients recovered from depression: a positron emission study with [(11)C]MDL 100,907. Am J Psychiatry 163(9):1580–1587

    PubMed  Google Scholar 

  • Bushe C, Shaw M, Peveler RC (2008) A review of the association between antipsychotic use and hyperprolactinaemia. J Psychopharmacol 22(2 Suppl):46–55

    Article  PubMed  Google Scholar 

  • de Paulis T (2001) M-100907 (Aventis). Curr Opin Investig Drugs 2(1):123–132

    PubMed  Google Scholar 

  • Farde L, Nordstrom AL, Wiesel FA, Pauli S, Halldin C, Sedvall G (1992) Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects. Arch Gen Psychiatry 49(7):538–544

    Article  CAS  PubMed  Google Scholar 

  • Farde L, Nyberg S, Oxenstierna G, Nakashima Y, Halldin C, Ericsson B (1995) Positron emission tomography studies on D2 and 5-HT2 receptor binding in risperidone-treated schizophrenic patients. J Clin Psychopharmacol 15(1 Suppl 1):19S–23S

    Article  CAS  PubMed  Google Scholar 

  • Frankle WG, Narendran R, Huang Y, Hwang DR, Lombardo I, Cangiano C et al (2005) Serotonin transporter availability in patients with schizophrenia: a positron emission tomography imaging study with [11C]DASB. Biol Psychiatry 57(12):1510–1516

    Article  CAS  PubMed  Google Scholar 

  • Gardell LR, Vanover KE, Pounds L, Johnson RW, Barido R, Anderson GT et al (2007) ACP-103, a 5-hydroxytryptamine 2A receptor inverse agonist, improves the antipsychotic efficacy and side-effect profile of haloperidol and risperidone in experimental models. J Pharmacol Exp Ther 322(2):862–870

    Article  CAS  PubMed  Google Scholar 

  • Grunder G, Carlsson A, Wong DF (2003) Mechanism of new antipsychotic medications: occupancy is not just antagonism. Arch Gen Psychiatry 60(10):974–977

    Article  PubMed  Google Scholar 

  • Grunder G, Landvogt C, Vernaleken I, Buchholz HG, Ondracek J, Siessmeier T et al (2006) The striatal and extrastriatal D2/D3 receptor-binding profile of clozapine in patients with schizophrenia. Neuropsychopharmacology 31(5):1027–1035

    Article  PubMed  Google Scholar 

  • Guttman M, Boileau I, Warsh J, Saint-Cyr JA, Ginovart N, McCluskey T et al (2007) Brain serotonin transporter binding in non-depressed patients with Parkinson’s disease. Eur J Neurol 14(5):523–528

    Article  CAS  PubMed  Google Scholar 

  • Hilton J, Yokoi F, Dannals RF, Ravert HT, Szabo Z, Wong DF (2000) Column-switching HPLC for the analysis of plasma in PET imaging studies. Nucl Med Biol 27(6):627–630

    Article  CAS  PubMed  Google Scholar 

  • Hinz R, Bhagwagar Z, Cowen PJ, Cunningham VJ, Grasby PM (2007) Validation of a tracer kinetic model for the quantification of 5-HT(2A) receptors in human brain with [(11)C]MDL 100,907. J Cereb Blood Flow Metab 27(1):161–172

    Article  CAS  PubMed  Google Scholar 

  • Hirani E, Sharp T, Sprakes M, Grasby P, Hume S (2003) Fenfluramine evokes 5-HT2A receptor-mediated responses but does not displace [11C]MDL 100907: small animal PET and gene expression studies. Synapse 50(3):251–260

    Article  CAS  PubMed  Google Scholar 

  • Kapur S, Zipursky R, Jones C, Remington G, Houle S (2000) Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. Am J Psychiatry 157(4):514–520

    Article  CAS  PubMed  Google Scholar 

  • Kessler RM, Ansari MS, Riccardi P, Li R, Jayathilake K, Dawant B, Meltzer HY (2005) Occupancy of striatal and extrastriatal dopamine D2/D3 receptors by olanzapine and haloperidol. Neuropsychopharmacology 30(12):2283–2289

    Article  CAS  PubMed  Google Scholar 

  • Kessler RM, Ansari MS, Riccardi P, Li R, Jayathilake K, Dawant B et al (2006) Occupancy of striatal and extrastriatal dopamine D2 receptors by clozapine and quetiapine. Neuropsychopharmacology 31(9):1991–2001

    Article  CAS  PubMed  Google Scholar 

  • Li P, Zhang Q, Robichaud AJ, Lee T, Tomesch J, Yao W, Beard JD, Snyder GL, Zhu H, Peng Y, Hendrick JP, Vanover KE, Davis RE, Mates S, Wennogle LP (2014) Discovery of a tetracyclic quinoxaline derivative as a potent and orally active multifunctional drug candidate for the treatment of neuropsychiatric and neurological disorders. J Med Chem 57(6):2670–2682

  • Mamo D, Graff A, Mizrahi R, Shammi CM, Romeyer F, Kapur S (2007) Differential effects of aripiprazole on D2, 5-HT2, and 5-HT1A receptor occupancy in patients with schizophrenia: a triple tracer PET study. Am J Psychiatry 164:1411–1417

    Article  PubMed  Google Scholar 

  • Marek GJ, Carpenter LL, McDougle CJ, Price LH (2003) Synergistic action of 5-HT2A antagonists and selective serotonin reuptake inhibitors in neuropsychiatric disorders. Neuropsychopharmacology 28(2):402–412

    Article  CAS  PubMed  Google Scholar 

  • Marek GJ, Martin-Ruiz R, Abo A, Artigas F (2005) The selective 5-HT2A receptor antagonist M100907 enhances antidepressant-like behavioral effects of the SSRI fluoxetine. Neuropsychopharmacology 30(12):2205–2215

    Article  CAS  PubMed  Google Scholar 

  • Mathis CA, Wang Y, Holt DP, Huang GF, Debnath ML, Klunk WE (2003) Synthesis and evaluation of 11C-labeled 6-substituted 2-arylbenzothiazoles as amyloid imaging agents. J Med Chem 46(13):2740–2754

    Article  CAS  PubMed  Google Scholar 

  • McCann UD, Szabo Z, Vranesic M, Palermo M, Mathews WB, Ravert HT et al (2008) Positron emission tomographic studies of brain dopamine and serotonin transporters in abstinent (+/-)3,4-methylenedioxymethamphetamine (“ecstasy”) users: relationship to cognitive performance. Psychopharmacology 200(3):439–450

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Meyer JH (2007) Imaging the serotonin transporter during major depressive disorder and antidepressant treatment. J Psychiatry Neurosci 32(2):86–102

    PubMed Central  PubMed  Google Scholar 

  • Meyer JH, Houle S, Sagrati S, Carella A, Hussey DF, Ginovart N et al (2004a) Brain serotonin transporter binding potential measured with carbon 11-labeled DASB positron emission tomography: effects of major depressive episodes and severity of dysfunctional attitudes. Arch Gen Psychiatry 61(12):1271–1279

    Article  CAS  PubMed  Google Scholar 

  • Meyer JH, Wilson AA, Sagrati S, Hussey D, Carella A, Potter WZ et al (2004b) Serotonin transporter occupancy of five selective serotonin reuptake inhibitors at different doses: an [11C]DASB positron emission tomography study. Am J Psychiatry 161(5):826–835

    Article  PubMed  Google Scholar 

  • Meyer JH, Wilson AA, Rusjan P, Clark M, Houle S, Woodside S et al (2008) Serotonin2A receptor binding potential in people with aggressive and violent behaviour. J Psychiatry Neurosci 33(6):499–508

    PubMed Central  PubMed  Google Scholar 

  • Nordstrom AL, Farde L, Wiesel FA, Forslund K, Pauli S, Halldin C et al (1993) Central D2-dopamine receptor occupancy in relation to antipsychotic drug effects: a double-blind PET study of schizophrenic patients. Biol Psychiatry 33(4):227–235

    Article  CAS  PubMed  Google Scholar 

  • Nordstrom AL, Farde L, Nyberg S, Karlsson P, Halldin C, Sedvall G (1995) D1, D2, and 5-HT2 receptor occupancy in relation to clozapine serum concentration: a PET study of schizophrenic patients. Am J Psychiatry 152(10):1444–1449

    Article  CAS  PubMed  Google Scholar 

  • Nyberg S, Eriksson B, Oxenstierna G, Halldin C, Farde L (1999) Suggested minimal effective dose of risperidone based on PET-measured D2 and 5-HT2A receptor occupancy in schizophrenic patients. Am J Psychiatry 156(6):869–875

    Article  CAS  PubMed  Google Scholar 

  • Poyurovsky M, Weizman R, Weizman A (2008) Aripiprazole’s receptor pharmacology and extrapyramidal side effects. Am J Psychiatry 165:398

    Article  PubMed  Google Scholar 

  • Pullar IA, Carney SL, Colvin EM, Lucaites VL, Nelson DL, Wedley S (2000) LY367265, an inhibitor of the 5-hydroxytryptamine transporter and 5-hydroxytryptamine(2A) receptor antagonist: a comparison with the antidepressant, nefazodone. Eur J Pharmacol 407(1–2):39–46

    Article  CAS  PubMed  Google Scholar 

  • Reimold M, Batra A, Knobel A, Smolka MN, Zimmer A, Mann K et al (2008) Anxiety is associated with reduced central serotonin transporter availability in unmedicated patients with unipolar major depression: a [11C]DASB PET study. Mol Psychiatry 13(6):606–613

    Article  CAS  PubMed  Google Scholar 

  • Reus GZ, Abelaira HM, Agostinho FR, Ribeiro KF, Vitto MF, Luciano TF et al (2012) The administration of olanzapine and fluoxetine has synergistic effects on intracellular survival pathways in the rat brain. J Psychiatr Res 46(8):1029–1035

    Article  PubMed  Google Scholar 

  • Ribeiro MJ, Ricard M, Bourgeois S, Lievre MA, Bottlaender M, Gervais P et al (2005) Biodistribution and radiation dosimetry of [11C]raclopride in healthy volunteers. Eur J Nucl Med Mol Imaging 32(8):952–958

    Article  PubMed  Google Scholar 

  • Rosell DR, Thompson JL, Slifstein M, Xu X, Frankle WG, New AS et al (2010) Increased serotonin 2A receptor availability in the orbitofrontal cortex of physically aggressive personality disordered patients. Biol Psychiatry 67(12):1154–1162

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Roth BL, Sheffler DJ, Kroeze WK (2004) Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia. Nat Rev 3:353–359

    CAS  Google Scholar 

  • Rummel-Kluge C, Komossa K, Schwarz S, Hunger H, Schmid F, Kissling W et al (2012) Second-generation antipsychotic drugs and extrapyramidal side effects: a systematic review and meta-analysis of head-to-head comparisons. Schizophr Bull 38(1):167–177

    Article  PubMed Central  PubMed  Google Scholar 

  • Schlaepfer TE, Pearlson GD, Wong DF, Marenco S, Dannals RF (1997) PET study of competition between intravenous cocaine and [11C]raclopride at dopamine receptors in human subjects. Am J Psychiatry 154(9):1209–1213

    Article  CAS  PubMed  Google Scholar 

  • Slifstein M, Hwang DR, Martinez D, Ekelund J, Huang Y, Hackett E et al (2006) Biodistribution and radiation dosimetry of the dopamine D2 ligand 11C-raclopride determined from human whole-body PET. J Nucl Med 47(2):313–319

    CAS  PubMed  Google Scholar 

  • Snyder SH (1976) The dopamine hypothesis of schizophrenia: focus on the dopamine receptor. Am J Psychiatry 133(2):197–202

    Article  CAS  PubMed  Google Scholar 

  • Snyder GL, Vanover KE, Zhu H, Miller DB, O’Callaghan JP, Tomesch J, Li P, et al (2015) Functional profile of a novel modulator of serotonin, dopamine, and glutamate neurotransmission. Psychopharmacology (Berl) 232(3):605–621

  • Tohen M, Case M, Trivedi MH, Thase ME, Burke SJ, Durell TM (2010) Olanzapine/fluoxetine combination in patients with treatment-resistant depression: rapid onset of therapeutic response and its predictive value for subsequent overall response in a pooled analysis of 5 studies. J Clin Psychiatry 71(4):451–462

    Article  CAS  PubMed  Google Scholar 

  • Vanover KE, Davis RE (2010) Role of 5-HT2A receptor antagonists in the treatment of insomnia. Nat Sci Sleep 2:139–150

    Article  PubMed Central  PubMed  Google Scholar 

  • Vanover KE, Davis RE, Ereshefsky L, Mates S (2014) Positive results for the treatment of schizophrenia: a randomized double-blind placebo- and active-controlled Phase 2 study. Schizophr Res 153:S278–S279

    Article  Google Scholar 

  • Vernaleken I, Janouschek H, Raptis M, Hellmann S, Veselinovic T, Brocheler A et al (2010) Dopamine D2/3 receptor occupancy by quetiapine in striatal and extrastriatal areas. Int J Neuropsychopharmacol 13(7):951–960

    Article  CAS  PubMed  Google Scholar 

  • Wadenberg ML, Salmi P, Jimenez P, Svensson T, Ahlenius S (1996) Enhancement of antipsychotic-like properties of the dopamine D2 receptor antagonist, raclopride, by the additional treatment with the 5-HT2 receptor blocking agent, ritanserin, in the rat. Eur Neuropsychopharmacol 6(4):305–310

    Article  CAS  PubMed  Google Scholar 

  • Wadenberg ML, Kapur S, Soliman A, Jones C, Vaccarino F (2000) Dopamine D2 receptor occupancy predicts catalepsy and the suppression of conditioned avoidance response behavior in rats. Psychopharmacology 150(4):422–429

    Article  CAS  PubMed  Google Scholar 

  • Wadenberg MG, Browning JL, Young KA, Hicks PB (2001) Antagonism at 5-HT(2A) receptors potentiates the effect of haloperidol in a conditioned avoidance response task in rats. Pharmacol Biochem Behav 68(3):363–370

    Article  CAS  PubMed  Google Scholar 

  • Wilson AA, Ginovart N, Hussey D, Meyer J, Houle S (2002) In vitro and in vivo characterisation of [11C]-DASB: a probe for in vivo measurements of the serotonin transporter by positron emission tomography. Nucl Med Biol 29(5):509–515

    Article  CAS  PubMed  Google Scholar 

  • Wong DF, Kuwabara H, Brašić JR, Stock T, Maini A, Gean EG et al (2013) Determination of dopamine D2 receptor occupancy by lurasidone using positron emission tomography in healthy male subjects. Psychopharmacology 229:245–252

    Article  CAS  PubMed  Google Scholar 

  • Yokoi F, Grunder G, Biziere K, Stephane M, Dogan AS, Dannals RF et al (2002) Dopamine D2 and D3 receptor occupancy in normal humans treated with the antipsychotic drug aripiprazole (OPC 14597): a study using positron emission tomography and [11C]raclopride. Neuropsychopharmacology 27(2):248–259

    Article  CAS  PubMed  Google Scholar 

  • Zhou Y, Endres CJ, Brašić JR, Huang SC, Wong DF (2003) Linear regression with spatial constraint to generate parametric images of ligand-receptor dynamic PET studies with a simplified reference tissue model. NeuroImage 18(4):975–989

    Article  PubMed  Google Scholar 

  • Zhou Y, Ye W, Brašić JR, Wong DF (2010) Multi-graphical analysis of dynamic PET. NeuroImage 49(4):2947–2957

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank the study team at PAREXEL Early Phase Clinical Unit in Baltimore, MD, especially Syed Faridi and the clinical team at The Johns Hopkins University School of Medicine, including Babar Hussain and Stephen Condouris. The authors also gratefully acknowledge the efforts of Robert F Dannals and his team in the Department of Radiology and Radiological Science at The Johns Hopkins University School of Medicine. The authors also thank Lawrence P Wennogle for his helpful comments on the manuscript. Importantly, the authors thank the volunteers for their participation in the study.

Funding

The clinical study described in this manuscript was sponsored and funded by Intra-Cellular Therapies, Inc. (ITI).

Authors’ contribution

The authors from ITI (RE Davis, KE Vanover, and S Mates) were involved in all aspects of the study, including the original concept and study design, the analysis and interpretation of the data, and the writing and approval of the manuscript.

Conflict of interest

Intra-Cellular Therapies, Inc. (ITI) sponsored this study. K Vanover and S Mates are employees of ITI. R Davis is a paid consultant to ITI. DR Goldwater is an employee of PAREXEL International, and L Gapasin was an employee of PAREXEL International at the time that this study was conducted. DF Wong discloses financial relationships with Intra-Cellular Therapies, Inc., Amgen, Avid, Bristol Myers Squibb, Lilly, Merck, Otsuka, Roche, Sanofi Aventis, and Wyeth. Y Zhou, JR Brašić, MR Guevara, B Bisuna, W Ye, V Raymont, A Kumar, and W Willis have no disclosures. ITI owns or controls the intellectual property that covers ITI-007, the investigational new drug evaluated in this study and described in this manuscript.

Author information

Author notes

  1. Lorena Gapasin

    Present address: Johns Hopkins University School of Medicine, Baltimore, MD, USA

Authors and Affiliations

  1. Intra-Cellular Therapies, Inc. (ITI), 3960 Broadway, 6th floor, New York, NY, 10032, USA

    Robert E. Davis, Kimberly E. Vanover & Sharon Mates

  2. 3-D Pharmaceutical Consultants, San Diego, CA, USA

    Robert E. Davis

  3. Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Yun Zhou, James R. Brašić, Maria Guevara, Blanca Bisuna, Weiguo Ye, Vanessa Raymont, William Willis, Anil Kumar & Dean F. Wong

  4. PAREXEL International, Baltimore, MD, USA

    Lorena Gapasin & D. Ronald Goldwater

Authors
  1. Robert E. Davis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kimberly E. Vanover
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yun Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. James R. Brašić
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maria Guevara
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Blanca Bisuna
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Weiguo Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Vanessa Raymont
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. William Willis
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Anil Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Lorena Gapasin
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. D. Ronald Goldwater
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Sharon Mates
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Dean F. Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kimberly E. Vanover.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Davis, R.E., Vanover, K.E., Zhou, Y. et al. ITI-007 demonstrates brain occupancy at serotonin 5-HT2A and dopamine D2 receptors and serotonin transporters using positron emission tomography in healthy volunteers. Psychopharmacology 232, 2863–2872 (2015). https://doi.org/10.1007/s00213-015-3922-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-015-3922-1

Keywords

Search

Navigation