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Research ArticleClinical Investigation

Phase 1 Evaluation of 11C-CS1P1 to Assess Safety and Dosimetry in Human Participants

Matthew R. Brier, Mahdjoub Hamdi, Jayashree Rajamanikam, Haiyang Zhao, Syahir Mansor, Lynne A. Jones, Farzaneh Rahmani, Saurabh Jindal, Deborah Koudelis, Joel S. Perlmutter, Dean F. Wong, Michael Nickels, Joseph E. Ippolito, Robert J. Gropler, Thomas H. Schindler, Richard Laforest, Zhude Tu and Tammie L.S. Benzinger
Journal of Nuclear Medicine November 2022, 63 (11) 1775-1782; DOI: https://doi.org/10.2967/jnumed.121.263189
Matthew R. Brier
1Department of Neurology, Washington University, St. Louis, Missouri;
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Mahdjoub Hamdi
2Mallinckrodt Institute of Radiology, Washington University, St. Louis, Missouri;
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Jayashree Rajamanikam
2Mallinckrodt Institute of Radiology, Washington University, St. Louis, Missouri;
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Haiyang Zhao
2Mallinckrodt Institute of Radiology, Washington University, St. Louis, Missouri;
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Syahir Mansor
2Mallinckrodt Institute of Radiology, Washington University, St. Louis, Missouri;
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Lynne A. Jones
2Mallinckrodt Institute of Radiology, Washington University, St. Louis, Missouri;
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Farzaneh Rahmani
2Mallinckrodt Institute of Radiology, Washington University, St. Louis, Missouri;
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Saurabh Jindal
2Mallinckrodt Institute of Radiology, Washington University, St. Louis, Missouri;
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Deborah Koudelis
2Mallinckrodt Institute of Radiology, Washington University, St. Louis, Missouri;
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Joel S. Perlmutter
1Department of Neurology, Washington University, St. Louis, Missouri;
2Mallinckrodt Institute of Radiology, Washington University, St. Louis, Missouri;
3Department of Neuroscience, Washington University, St. Louis, Missouri;
4Department of Physical and Occupational Therapy, Washington University, St. Louis, Missouri; and
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Dean F. Wong
1Department of Neurology, Washington University, St. Louis, Missouri;
2Mallinckrodt Institute of Radiology, Washington University, St. Louis, Missouri;
3Department of Neuroscience, Washington University, St. Louis, Missouri;
5Department of Psychiatry, Washington University, St. Louis, Missouri
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Michael Nickels
2Mallinckrodt Institute of Radiology, Washington University, St. Louis, Missouri;
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Joseph E. Ippolito
2Mallinckrodt Institute of Radiology, Washington University, St. Louis, Missouri;
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Robert J. Gropler
2Mallinckrodt Institute of Radiology, Washington University, St. Louis, Missouri;
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Thomas H. Schindler
2Mallinckrodt Institute of Radiology, Washington University, St. Louis, Missouri;
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Richard Laforest
2Mallinckrodt Institute of Radiology, Washington University, St. Louis, Missouri;
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Zhude Tu
2Mallinckrodt Institute of Radiology, Washington University, St. Louis, Missouri;
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Tammie L.S. Benzinger
2Mallinckrodt Institute of Radiology, Washington University, St. Louis, Missouri;
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  • FIGURE 1.
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    FIGURE 1.

    Heart rate response to 11C-CS1P1 injection: stable heart rate before injection, 5 min after injection, and at discharge, as captured on 12-lead electrocardiogram (P > 0.1).

  • FIGURE 2.
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    FIGURE 2.

    Qualitative biodistribution of 11C-CS1P1. (A) Summed activity PET/CT images for representative male and female participants. (B) Decay-corrected activity is high in liver early in scanning session but is clearly concentrated in gallbladder later in scans, compatible with hepatobiliary excretion.

  • FIGURE 3.
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    FIGURE 3.

    Qualitative biodistribution in typical participant. Summed activity on 11C-CS1P1 PET/CT images is expressed as SUV. (A–D) Uptake in brain is highest in gray matter and relatively low in white matter. Increased update is seen in salivary glands (B), left ventricle (C), and liver (D). Common bile duct is appreciated (arrowhead). (E) Parenchymal uptake within kidneys is seen but without activity in collecting system and with scant amounts of small-bowel uptake.

  • FIGURE 4.
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    FIGURE 4.

    Non–decay-corrected (blue) and decay-corrected (red) time–activity curves for organs showing measurable signal. Axes vary in scale by row. Shaded area indicates first 5 min of scan, when dynamic images over heart were acquired. %ID = percentage injected dose.

  • FIGURE 5.
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    FIGURE 5.

    Summed brain activity images from 20 to 60 min after injection in single participant. Units are SUV based on measured body weight.

  • FIGURE 6.
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    FIGURE 6.

    Correlation of 11C-CS1P1 uptake with S1PR1 expression. Regional SUVs were extracted from summed activity image using FreeSurfer and then z-transformed. Matching S1PR1 RNA expression was extracted from Allen Brain Atlas and correlated. Tracer activity and RNA expression correlated significantly, thus providing preliminary evidence that 11C-CS1P1 engages its target.

  • FIGURE 7.
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    FIGURE 7.

    Lack of correlation between 11C-CS1P1 uptake and S1PR2–5 expression. Scatterplots in same style as Figure 6 are shown. All correlations are smaller than correlation between 11C-CS1P1 and S1PR1.

Tables

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    TABLE 1.

    Participant Demographics and Injected Dose

    DemographicParticipant no.
    12345678910
    SexMFFMMMMFFF
    Age (y)28234061593437272739
    Height (cm)185.4177.8165.1167.6185.4175.3172.7165.1162.6175.3
    Weight (kg)88.9105.769.467.1104.8106.174.8117.950.3117.5
    Injected dose
     MBq266.499.9170.2247.9240.5296.0225.7210.9362.6144.3
     mCi7.22.74.66.76.58.06.15.79.83.9
    Injected mass (μg)4.704.563.292.882.693.402.943.272.780.98
    • View popup
    TABLE 2.

    Integrated Time–Activity Curve Values (Minutes)

    SiteParticipant no.AverageSD
    12345678910
    Liver6.455.156.856.756.167.417.364.247.765.556.371.11
    Brain0.450.390.610.400.380.430.490.290.270.430.410.10
    Kidney1.010.791.220.900.781.150.990.521.090.710.920.22
    Small bowel0.730.660.831.000.880.770.980.350.740.940.790.19
    Lung0.290.240.240.230.200.310.270.210.250.190.240.04
    Left ventricular wall0.160.850.190.280.270.310.310.120.280.180.300.21
    Spleen0.100.080.120.090.100.100.120.070.070.170.100.03
    Gallbladder0.010.020.020.010.010.020.030.010.030.020.020.01
    Urinary bladder0.010.000.020.010.020.060.010.010.010.010.010.02
    Remainder16.8219.0616.2317.6818.4516.8515.5122.2716.9919.6517.951.98
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    TABLE 3.

    Radiation Dosimetry, Female

    SiteParticipant no.MeanSD
    238910
    Adrenals5.686.565.286.776.076.070.61
    Brain2.062.891.751.572.252.100.51
    Breasts2.442.162.622.292.442.390.17
    Esophagus3.793.473.463.773.523.600.16
    Eyes2.201.982.501.952.282.180.23
    Gallbladder wall5.886.545.017.285.926.130.84
    Left colon3.473.073.553.213.403.340.20
    Small intestine3.263.133.463.253.433.310.14
    Stomach wall3.503.313.613.483.563.490.11
    Right colon12.4014.708.3513.5016.4013.073.03
    Rectum2.822.473.252.572.922.810.31
    Heart wall16.005.033.936.704.947.324.95
    Kidneys14.7021.9010.4020.0013.7016.144.72
    Liver20.3026.6016.9030.0021.8023.125.19
    Lungs3.123.002.733.222.782.970.21
    Ovaries2.972.643.362.743.082.960.29
    Pancreas4.755.044.685.394.954.960.28
    Salivary glands2.352.092.662.092.422.320.24
    Red marrow2.622.422.812.542.672.610.15
    Osteogenic cells2.262.062.482.132.312.250.16
    Spleen4.686.084.084.437.685.391.49
    Thymus3.252.633.132.832.942.960.24
    Thyroid2.522.182.772.292.522.460.23
    Urinary bladder wall2.392.262.862.192.522.440.26
    Uterus2.892.563.302.663.002.880.29
    Total body3.303.223.393.373.383.330.07
    Effective dose (18)4.134.323.694.494.284.180.30
    • Data are single-participant individual organ doses (μSv/MBq).

    • View popup
    TABLE 4.

    Radiation Dosimetry, Male

    SiteParticipant no.MeanSD
    14567
    Adrenals5.715.805.476.285.975.850.30
    Brain1.991.801.771.902.091.910.13
    Esophagus2.692.852.822.902.762.800.08
    Eyes1.621.691.751.621.521.640.09
    Gallbladder wall6.647.216.507.607.897.170.60
    Left colon2.602.732.752.702.542.660.09
    Small Intestine2.702.892.892.802.682.790.10
    Stomach wall2.812.952.942.992.842.910.08
    Right colon13.7017.8016.0014.4017.4015.861.80
    Rectum2.112.222.302.151.982.150.12
    Heart wall4.075.615.476.146.035.460.83
    Kidneys16.3014.9013.1018.4016.1015.761.95
    Liver19.9020.9019.1022.8022.6021.061.63
    Lungs2.552.442.312.782.602.540.18
    Pancreas3.373.583.523.603.473.510.09
    Prostate2.142.262.332.202.022.190.12
    Salivary glands1.841.911.981.841.731.860.09
    Red marrow2.002.092.122.081.952.050.07
    Osteogenic cells1.871.951.991.911.791.900.08
    Spleen4.474.174.264.365.004.450.33
    Testes1.721.811.891.731.591.750.11
    Thymus2.202.362.392.362.222.310.09
    Thyroid1.952.032.091.991.841.980.09
    Urinary bladder wall2.022.122.362.591.922.200.27
    Total body2.392.512.522.502.372.460.07
    Effective dose (18)3.343.633.443.643.653.540.14
    • Data are single-participant individual organ doses (μSv/MBq).

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Journal of Nuclear Medicine: 63 (11)
Journal of Nuclear Medicine
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November 1, 2022
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Phase 1 Evaluation of 11C-CS1P1 to Assess Safety and Dosimetry in Human Participants
Matthew R. Brier, Mahdjoub Hamdi, Jayashree Rajamanikam, Haiyang Zhao, Syahir Mansor, Lynne A. Jones, Farzaneh Rahmani, Saurabh Jindal, Deborah Koudelis, Joel S. Perlmutter, Dean F. Wong, Michael Nickels, Joseph E. Ippolito, Robert J. Gropler, Thomas H. Schindler, Richard Laforest, Zhude Tu, Tammie L.S. Benzinger
Journal of Nuclear Medicine Nov 2022, 63 (11) 1775-1782; DOI: 10.2967/jnumed.121.263189

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Phase 1 Evaluation of 11C-CS1P1 to Assess Safety and Dosimetry in Human Participants
Matthew R. Brier, Mahdjoub Hamdi, Jayashree Rajamanikam, Haiyang Zhao, Syahir Mansor, Lynne A. Jones, Farzaneh Rahmani, Saurabh Jindal, Deborah Koudelis, Joel S. Perlmutter, Dean F. Wong, Michael Nickels, Joseph E. Ippolito, Robert J. Gropler, Thomas H. Schindler, Richard Laforest, Zhude Tu, Tammie L.S. Benzinger
Journal of Nuclear Medicine Nov 2022, 63 (11) 1775-1782; DOI: 10.2967/jnumed.121.263189
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