Research ArticleNeurology

PET Imaging Evaluation of Four σ1 Radiotracers in Nonhuman Primates

Evan Baum, Zhengxin Cai, Frederic Bois, Daniel Holden, Shu-fei Lin, Teresa Lara-Jaime, Michael Kapinos, Yuanyuan Chen, Winnie Deuther-Conrad, Steffen Fischer, Sladjana Dukic-Stefanovic, Paul Bunse, Bernhard Wünsch, Peter Brust, Hongmei Jia and Yiyun Huang
Journal of Nuclear Medicine June 2017, 58 (6) 982-988; DOI: https://doi.org/10.2967/jnumed.116.188052

Article Figures & Data

Figures

  • FIGURE 1.
    FIGURE 1.

    Structures of previous S1R tracers 18F-FPS, 18F-FBP, 11C-SA4503, and 18F-FTC-146, and spirocyclic piperidine derivatives 18F-1 to 18F-4, with in vitro Ki values for S1R (10–15).

  • FIGURE 2.
    FIGURE 2.

    Syntheses of the 4 radiotracers. Reagents and conditions: (a) 18F−, Kryptofix 2.2.2, K2CO3, MeCN, 85°C, 20 min; (b) 18F−, Kryptofix 2.2.2, K2CO3, MeCN, 95°C, 20 min; (c) 18F−, Kryptofix 2.2.2, K2CO3, MeCN, 80°C, 10 min; and (d) Cs2CO3, DMF, 110°C, 10 min.

  • FIGURE 3.
    FIGURE 3.

    Plasma analysis of the 4 radiotracers in the same monkey. (A) Total radioactivity in plasma over time. (B) Time course of parent fraction from 4-h baseline and 2-h blocking scans with SA4503.

  • FIGURE 4.
    FIGURE 4.

    Time–activity curves of 18F-1 (A), 18F-2 (B), 18F-3 (C), and 18F-4 (D) in selected brain regions from baseline scans in the same monkey. For clarity of presentation, not all brain regions are displayed.

  • FIGURE 5.
    FIGURE 5.

    Time stability of VT for the 4 tracers. Times refer to midtimes of each 10-min acquisition. Data from 60 to 240 min were analyzed in 30-min increments, and VT expressed as percentage of value derived with complete dataset (240 min). Each point is average VT from 16 ROIs. Deviation from 100% of mean value indicates bias associated with shorter scanning times, whereas SD indicates regional error associated with shorter scanning times. Bias and error for 18F-3 at 60 min was too large (>10,000%) to display.

  • FIGURE 6.
    FIGURE 6.

    PET images (coronal, transverse, and sagittal views) summed from 30 to 45 min of baseline scans for 18F-1 (A), 18F-2 (B), 18F-3 (C), and 18F-4 (D).

Tables

  • TABLE 1

    Comparison of Ki, Selectivity, Lipophilicity, and fP

    LigandKi (σ-1)Ki (σ-2)SelectivityLog DfP
    18F-10.57 nM*1,650 nM*2,895*2.82%
    18F-22.3 nM*897 nM*390*2.82%
    18F-30.79 nM†277 nM†351†2.558%
    18F-42.3 nM†327 nM†142†2.518%

    • ↵* Taken from Holl et al. (15).

    • ↵† Taken from Li et al. (14).

  • TABLE 2

    Comparison of 1TC-Derived VT Values for the 4 Tracers Across Different Brain Regions

    VT (mL∙cm−3)
    ConditionAmygdalaCaudateCerebellumCingulate cortexFrontal cortexHippocampusOccipital cortexPutamenTemporal cortexThalamus
    18F-1 baseline152.8180.8174.9291.4215.5192.8174.1199215.7127.7
    18F-2 baseline14.6 (31.6)*13.5 (28.4)*13.6 (30.2)*19.6 (37.9)*17.8 (35.1)*16.4 (33.5)*14.6 (30.0)*14.9 (31.8)*16.5 (32.6)*12.2 (30.2)*
    18F-3 baseline574.9479.3507.81351.91099.7575.8786.9530.3916.8471
    18F-4 baseline44.4 (42.3)*36.7 (35.7)*35.3 (32.7)*57.9 (56.8)*46.5 (47.6)*48.2 (46.5)*38.2 (31.7)*38.1 (35.9)*44.4 (40.6)*35.3 (38.9)*
    18F-2 SA4503 block6.27.17.68.68.37.588.88.37.2
    18F-4 SA4503 block9.410.39.91211.99.810.811.911.59.8

    • ↵* Baseline VT values in 2 different female monkeys are noted in parentheses for 18F-2 and 18F-4.

  • TABLE 3

    1TC-Derived BPND Values of 18F-2 and 18F-4 Across Different Brain Regions

    BPND
    RadioligandAmygdalaCaudateCerebellumCingulate cortexFrontal cortexHippocampusOccipital cortexPutamenTemporal cortexThalamus
    18F-21.130.960.981.851.591.381.131.171.400.77
    18F-43.762.942.785.213.994.163.093.083.762.78

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