Research ArticleBasic Science Investigation

Robust Quantification of Phosphodiesterase-4D in Monkey Brain with PET and 11C-Labeled Radioligands That Avoid Radiometabolite Contamination

Meijuan Jiang, Shiyu Tang, Madeline D. Jenkins, Adrian C. Lee, Bruny Kenou, Carson Knoer, Jose Montero Santamaria, Shawn Wu, Jeih-San Liow, Sami S. Zoghbi, Paolo Zanotti-Fregonara, Robert B. Innis, Sanjay Telu and Victor W. Pike
Journal of Nuclear Medicine May 2024, 65 (5) 788-793; DOI: https://doi.org/10.2967/jnumed.123.266750

Article Figures & Data

Figures

  • Figure
  • FIGURE 1.
    FIGURE 1.

    Chemical structures of T1650 and 5 new PDE4D radioligand candidates. Asterisks denote sites for 11C labeling.

  • FIGURE 2.
    FIGURE 2.

    Illustration of radioligand production and evaluation. DMF = dimethylformamide.

  • FIGURE 3.
    FIGURE 3.

    (A and B) Time–activity curves after injection of [11C]JMJ-81 for monkey brain (A) and unchanged radioligand in plasma (B) at baseline and after block by rolipram (0.5 mg/kg, intravenously) in same monkey. (C) VT values at 90 min after injection of [11C]JMJ-81 across monkey brain regions at baseline and after block by rolipram (0.5 mg/kg intravenously). SUV is calculated as radioactivity in brain (Bq) per g of brain divided by injected activity (Bq) per g of body weight (36).

  • FIGURE 4.
    FIGURE 4.

    (A and B) Lassen plots for whole brain in 2 monkeys for [11C]JMJ-81 (A) and [11C]JMJ-129 (B), based on VT measures from 2-tissue-compartment modeling. (C and D) VT time-stability curves for whole brain, frontal cortex, and cerebellum for [11C]JMJ-81 (C) and [11C]JMJ-129 (D) from 2 monkeys. VT values are normalized to end of scan values. Rolipram dose was 0.5 mg/kg for monkey 1 in [11C]JMJ-81 experiment only. Other experiments used rolipram at 0.2 mg/kg. WB = whole brain.

  • FIGURE 5.
    FIGURE 5.

    (A) VT estimated by Logan analysis of regional monkey brain data for [11C]JMJ-81 and [11C]JMJ-129 at baseline and after PDE4D block with BPN14770 (3 mg/kg, intravenously). (B) PET images of radioactivity concentration (SUV) for [11C]JMJ-81 and [11C]JMJ-129 in monkey brain at baseline and after PDE4D block. Radioactivity concentrations were averaged from 20 to 60 min.

  • FIGURE 6.
    FIGURE 6.

    (A) Relative in vitro stabilities of radioligands ([11C]T1650, [11C]JMJ-81, and [11C]JMJ-129) after incubation with fresh rat whole blood, plasma, and homogenized fresh brain tissues for at least 30 min at 37°C (n = 1). (B) Relative ex vivo stability of radioligands in rat brain and plasma at 30 min after injection (n = 3). (C) Representative radiochromatograms for HPLC of plasma and brain harvested from monkey at 30 min after injection of [11C]JMJ-81.

Tables

  • TABLE 1.

    Physicochemical Properties, Pharmacologic Properties, and PET Imaging Parameters in Monkeys of 5 Selected PDE4D Radioligands and Previously Reported (24) PDE4D Ligand [11C]T1650

    RadioligandCNS PET MPOEC50 (nM)Selectivity (B/D)cLogD7.4mLogD7.4fp (%)VNDBPND
    PDE4DPDE4B
    [11C]T16503.93.511203203.482.896.7 ± 0.73.581.2
    [11C]JMJ-814.22.7 ± 0.5521 ± 461932.903.155.7 ± 0.83.3, 3.41.2, 0.61
    [11C]JMJ-1294.31.4 ± 0.011070 ± 147932.903.285.8 ± 0.73.5, 4.32.4, 1.0
    [11C]JMJ-1684.12.15132423.172.736.8 ± 0.54.0, 5.30.69, 0.27
    [11C]JMJ-1694.11.15935593.172.828.4 ± 0.85.2, 3.90.57, 2.2
    [11C]JMJ-1823.42.013406703.283.332.9 ± 0.24.3, 3.70.59, 0.44

    • CNS PET MPO = multiparameter optimization value for central nervous system PET radioligand (estimated as in (26)); EC50 = half-maximal effective concentration; B/D = ratio of EC50 for PDE4B over that for PDE4D; cLogD7.4 = computed lipophilicity for n-octanol/buffer solution distribution coefficient at pH 7.4; mLogD7.4 = experimentally measured lipophilicity; fp = plasma free fraction; PDE4B = PDE4B1–S133D, dimeric isoform of PDE4B that contains UCR1 mutation (S133D) that mimics protein kinase A phosphorylation.

    • Data for multiparameter optimization for central nervous system PET radioligand scoring (i.e., PDE4D EC50, PDE4B EC50, B/D, and clogD7.4) are sourced from our previous reports (24,25). Binding assays were repeated (n = 2) for JMJ-81 and JMJ-129. cLogD7.4 values were calculated with Pallas software; mlogD7.4 values were measured with radioligands (n = 6). Plasma free fraction was measured and averaged with monkey plasma (n = 4 or greater). VND and BPND were measured in 2 monkeys except in one monkey for [11C]T1650, in which rolipram was used as blocking agent at 0.5 mg/kg for first monkey studied with [11C]JMJ-81 and at 0.2 mg/kg for all other experiments.

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