Research ArticleClinical Investigation

Contribution of SPECT Measurements of D2 and 5-HT2A Occupancy to the Clinical Development of the Antipsychotic SB-773812

Ana M. Catafau, Santiago Bullich, Gianluca Nucci, Clare Burgess, Frank Gray, Emilio Merlo-Pich and on behalf of the Barcelona Clinical Imaging in Psychiatry Group
Journal of Nuclear Medicine April 2011, 52 (4) 526-534; DOI: https://doi.org/10.2967/jnumed.110.081885

Article Figures & Data

Figures

  • FIGURE 1.
    FIGURE 1.

    Selected MRI and coregistered SPECT slices at basal ganglia level (top and middle rows) and at cerebellum level (bottom row), showing representative ROIs drawn on basal ganglia and occipital cortex for D2 quantification (top row) and on cortical regions and cerebellum for 5-HT2A quantification (middle and bottom rows). IBZM = iodobenzamide.

  • FIGURE 2.
    FIGURE 2.

    Individual values of D2 and 5-HT2A occupancy from study A. 5-HT2A occupancy values are mean of all cortical regions.

  • FIGURE 3.
    FIGURE 3.

    Coregistered SPECT/MR images from representative healthy volunteers (study A, left) and patients with schizophrenia (studies B [right top] and C [right bottom]). Percentages of D2 and 5-HT2A occupancy values are shown for each individual case. 5-HT2A occupancy values are mean of all cortical regions.

  • FIGURE 4.
    FIGURE 4.

    Individual 5-HT2A occupancy data from studies A and B and corresponding Emax model fitting. Dashed lines correspond to 95% confidence interval. 5-HT2A occupancy values are mean of all cortical regions.

  • FIGURE 5.
    FIGURE 5.

    Individual D2 occupancy data from studies A, B, and C with corresponding Emax model fitting. Dashed lines correspond to 95% confidence interval.

  • FIGURE 6.
    FIGURE 6.

    Individual D2 occupancy values at Tmax and Ttrough from subjects in study C. Dashed lines correspond to patients on risperidone.

Tables

  • TABLE 1

    Summary of Human SPECT Studies Performed to Contribute to SB-773812 Development

    Study A, healthy volunteers (n = 27; all men; 26 ± 5 y)Study B, patients with chronic schizophrenia (n = 14; 10 men; 33 ± 7 y)Study C, patients with exacerbated schizophrenia ± (n = 12; all men; 36 ± 8 y)
    ParameterCohort 1 (n = 9)Cohort 2 (n = 9)Cohort 3 (n = 9)
    SB-773812 dose48 mg (single)56 mg (single)56 mg (single)56 mg/d, 16–18 d (steady state)100 mg/d, 18–21 d (n = 9)
    Risperidone dose6 mg/d (n = 3)
    Target (receptor)D2D25-HT2AD2 + 5-HT2AD2
    Scans (2/subject, 48 h apart)Baseline postdosePostdose 123I-iodobenzamide, postdose 123I-R91150Postdose Cmax, postdose Ctrough
    Scan time after doseTmax (6 ± 2 h) (n = 5/cohort), Ttrough (24 ± 4 h) (n = 4/cohort)12 ± 4 hTmax (6 ± 2 h) (n = 10), Ttrough (24 ± 4 h) (n = 8)
    % receptor occupancy formula (×100)(1 − [SURpostdose/SURbaseline])(1 − [SURpostdose/SURHV])(1 − [SURpostdose/SURHV])
    Plasma concentration over time (pharmacokinetics)YesYesYes

    • HV = healthy volunteers.

  • TABLE 2

    Mean D2 Occupancy and Plasma Concentrations Measured Over Time in Studies A, B, and C

    StudyDrugDrug dosePlasma concentration during scan∼Tmax (ng/mL)% D2 occupancy at Tmax (6 ± 2 h)Plasma concentration during scan∼Ttrough (ng/mL)% D2 occupancy at Ttrough (24 ± 4 h)
    ASB-77381248/56 mg21.0 ± 6.7 (n = 10)16.4 ± 8.4 (n = 10)17.8 ± 5.3 (n = 8)21.3 ± 7.8 (n = 4)
    BSB-77381256 mg/d89.0 ± 27.1 (n = 12)42.7 ± 25.2 (n = 12)NANA
    CSB-773812100 mg/d125.1 ± 23.7 (n = 7)60.3 ± 13.3 (n = 7)98.8 ± 34.5 (n = 5)55.1 ± 14.9 (n = 5)
    Risperidone6 mg/d55.5 ± 31.9 (n = 3)83.6 ± 3.4 (n = 3)26.1 ± 20.0 (n = 3)64.4 ± 3.6 (n = 3)

    • Risperidone plasma concentration reported as active moiety (i.e., risperidone + 9-OH-risperidone).

    • NA = not available.

  • TABLE 3

    Estimated EC50 Values (Mean ± SE) for Both D2 and 5-HT2A Receptor Targets with Between-Subject Variability from Each Study and from All Studies Pooled Together

    ParameterStudy AStudy BStudy CPooled
    EC50 for D2 (ng/mL)90.7 ± 63.898.3 ± 15.681.2 ± 8.992.7 ± 13.5
    Between-subject variability in D2 EC50NA82%45%73%
    EC50 for 5-HT2A (ng/mL)2.3 ± 0.41.6 ± 0.8NA2.1 ± 0.5
    Between-subject variability in 5-HT2A EC5056%147%NA71%

    • NA = not available.

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