Research ArticleNeurology

Dopamine D1 Receptor Agonist PET Tracer Development: Assessment in Nonhuman Primates

Olivier Barret, Lei Zhang, David Alagille, Cristian C. Constantinescu, Christine Sandiego, Caroline Papin, Jenna M. Sullivan, Thomas Morley, Vincent M. Carroll, John Seibyl, Jianqing Chen, Chewah Lee, Anabella Villalobos, David Gray, Timothy J. McCarthy and Gilles Tamagnan
Journal of Nuclear Medicine September 2021, 62 (9) 1307-1313; DOI: https://doi.org/10.2967/jnumed.120.256008

Article Figures & Data

Figures

  • Figure
  • FIGURE 1.
    FIGURE 1.

    Profile of D1R agonist PET ligand lead MNI-968. AB = apical to basolateral; BA = basolateral to apical; CNS = central nervous system; cFub = fraction unbound in brain; EC50 = half-maximal effective concentration; Emax = maximal effect; hD1 = human D1; hD2 = human D2; IC50 = half-maximal inhibitory concentration; Ki = inhibition constant; MDR1 = multi-drug resistance 1; MPO = multiparameter optimization; rD1 = rat D1; Papp = apparent permeability; RRCK = Ralph Russ canine kidney assay.

  • FIGURE 2.
    FIGURE 2.

    Radiosynthesis of 18F-MNI-800 and 18F-MNI-968.

  • FIGURE 3.
    FIGURE 3.

    Parent fraction profile in arterial plasma after intravenous administration of 18F-MNI-800 (mean ± SD, n = 4) or 18F-MNI-968 (mean ± SD, n = 4).

  • FIGURE 4.
    FIGURE 4.

    (Left) Average PET images from 30 to 90 min after injection for rhesus macaque (NHP A) in transverse plane of 18F-MNI-800 at baseline and after dosing with SCH-23390 at 0.5 mg/kg (occupancy of ∼85%) and of 18F-MNI-968 at baseline and after dosing with PF-2562 at 1.2 mg/kg (occupancy of ∼40%). (Right) Time–activity curves in some brain regions for same rhesus macaque for studies with 18F-MNI-800 and 18F-MNI-968. Caud. Nucl. = caudate nucleus; Glob. Pall. = globus pallidus; Nucl. Acc. = nucleus accumbens.

  • FIGURE 5.
    FIGURE 5.

    (A and C) Representative time–activity curves at baseline for rhesus macaque (NHP B) in some brain regions after bolus injection of 18F-MNI-968, showing 2T compartment model fits (A) and SRTM fits (C). (B and D) Graphical analysis with LGA with plasma input function (t* = 15 min) (B) and NI-LGA with reference region input function (t* = 10 min) (D). Caud. Nucl. = caudate nucleus; Cp = activity concentration in plasma; Cref = activity concentration in reference region; Ct = activity concentration in region of interest; Glob. Pall. = globus pallidus; Nucl. Acc. = nucleus accumbens; Thal. = thalamus.

  • FIGURE 6.
    FIGURE 6.

    (A) Within-animal comparison (n = 2) of 18F-MNI-800 and 18F-MNI-968 2T VT estimates. (B) Comparison of 18F-MNI-968 VT estimates across models (n = 3). (C) Comparison of 18F-MNI-968 BPND estimates across models (n = 3). 1T = 1 tissue compartment.

  • FIGURE 7.
    FIGURE 7.

    (A) SCH-23390 plasma levels for 4 doses, with 18F-MNI-800 injection at 25 min after drug administration. (B) Striatal D1R occupancy against average plasma levels between 25 and 145 min after administration of SCH-23390. EC50 = half-maximal effective concentration.

Tables

  • TABLE 1

    Summary of Scans with 18F-MNI-800 or 18F-MNI-968

    SpeciesNHP no.18F-MNI-80018F-MNI-968
    RhesusATest, retest, SCH23390 (0.5 and 0.1 mg/kg)Test, retest,* PF-2562 (1.2 mg/kg)*
    BTest, retest, SCH23390 (0.2 and 0.03 mg/kg), dosimetryBaseline
    CDosimetryBaseline,* PF-2562 (1.2 mg/kg)*
    CynomolgusDBaselineBaseline
    EBaseline
    FBaseline

    • ↵* 90-min scan.

    • Scans are 120 min unless otherwise indicated.

  • TABLE 2

    18F-MNI-800 VT and BPND in Pooled Rhesus and Cynomolgus Macaques

    VTBPND
    Region2TLGA2TLGASRTMNI-LGA
    Striatum3.6 ± 0.3 (8%)3.5 ± 0.3 (8%)0.86 ± 0.10 (11%)0.83 ± 0.08 (9%)0.83 ± 0.07 (8%)0.83 ± 0.07 (8%)
    Caudate3.5 ± 0.4 (11%)3.4 ± 0.4 (11%)0.81 ± 0.11 (14%)0.78 ± 0.10 (12%)0.78 ± 0.09 (11%)0.78 ± 0.09 (12%)
    Putamen3.7 ± 0.3 (7%)3.6 ± 0.3 (7%)0.91 ± 0.14 (15%)0.88 ± 0.12 (13%)0.89 ± 0.11 (12%)0.89 ± 0.11 (13%)
    Nucleus accumbens2.9 ± 0.2 (7%)2.8 ± 0.2 (7%)0.48 ± 0.03 (6%)0.46 ± 0.02 (5%)0.45 ± 0.02 (5%)0.46 ± 0.02 (5%)
    Globus pallidus2.9 ± 0.3 (9%)2.8 ± 0.3 (9%)0.50 ± 0.06 (13%)0.48 ± 0.06 (12%)0.48 ± 0.06 (12%)0.48 ± 0.05 (11%)
    Thalamus2.4 ± 0.2 (9%)2.4 ± 0.2 (8%)0.25 ± 0.06 (22%)0.25 ± 0.04 (17%)0.26 ± 0.04 (16%)0.26 ± 0.04 (16%)
    Frontal cortex2.3 ± 0.0 (0%)2.2 ± 0.0 (1%)0.24 ± 0.04 (18%)0.20 ± 0.05 (24%)0.20 ± 0.05 (23%)0.20 ± 0.05 (25%)
    Cerebellum1.9 ± 0.1 (7%)1.9 ± 0.1 (6%)

    • Data are mean ± SD, followed by coefficient of variation in parentheses (n = 4).

  • TABLE 3

    18F-MNI-968 VT and BPND in Pooled Rhesus and Cynomolgus Macaques

    VTBPND
    Region2TLGA2TLGASRTMNI-LGA
    Striatum4.1 ± 0.2 (4%)4.0 ± 0.2 (4%)1.14 ± 0.05 (5%)1.07 ± 0.02 (2%)1.07 ± 0.03 (2%)1.08 ± 0.03 (3%)
    Caudate4.0 ± 0.3 (8%)3.9 ± 0.3 (8%)1.08 ± 0.12 (11%)1.02 ± 0.09 (9%)1.06 ± 0.09 (8%)1.06 ± 0.08 (8%)
    Putamen4.3 ± 0.2 (4%)4.1 ± 0.2 (4%)1.20 ± 0.09 (8%)1.13 ± 0.10 (9%)1.11 ± 0.08 (7%)1.12 ± 0.08 (8%)
    Nucleus accumbens3.2 ± 0.2 (5%)3.1 ± 0.2 (6%)0.65 ± 0.02 (4%)0.61 ± 0.00 (0%)0.59 ± 0.07 (12%)0.60 ± 0.07 (12%)
    Globus pallidus3.2 ± 0.6 (18%)3.1 ± 0.5 (18%)0.65 ± 0.20 (31%)0.60 ± 0.21 (35%)0.58 ± 0.18 (31%)0.58 ± 0.18 (31%)
    Thalamus2.6 ± 0.2 (9%)2.6 ± 0.2 (9%)0.35 ± 0.04 (13%)0.33 ± 0.04 (13%)0.29 ± 0.05 (19%)0.29 ± 0.06 (20%)
    Frontal cortex2.6 ± 0.1 (2%)2.4 ± 0.1 (2%)0.33 ± 0.08 (25%)0.27 ± 0.04 (15%)0.28 ± 0.05 (17%)0.28 ± 0.05 (18%)
    Cerebellum1.9 ± 0.1 (6%)1.9 ± 0.1 (5%)

    • Data are mean ± SD, followed by coefficient of variation in parentheses (n = 3 for 2T and LGA, and n = 5 for SRTM and NI-LGA).

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