Research ArticleBasic Science Investigation

Development and Preclinical Evaluation of [211At]PSAt-3-Ga: An Inhibitor for Targeted α-Therapy of Prostate Cancer

Mohamed El Fakiri, Nawal Ayada, Marius Müller, Lars Hvass, Teodor H. Gamzov, Anne Skovsbo Clausen, Nicolas M. Geis, Nils Steinacker, Ellinor Hansson, Sture Lindegren, Emma Aneheim, Holger Jensen, Ann-Christin Eder, Andreas I. Jensen, Christian B.M. Poulie, Andreas Kjaer, Matthias Eder and Matthias M. Herth
Journal of Nuclear Medicine February 2024, jnumed.123.267043; DOI: https://doi.org/10.2967/jnumed.123.267043

Article Figures & Data

Figures

  • Figure
  • FIGURE 1.
    FIGURE 1.

    Design rationale of reported series. Compound selected as lead candidate, [211At]-PSAt-3, is used as example. EuK = glutamate–urea–lysine; PK = pharmacokinetics.

  • FIGURE 2.
    FIGURE 2.

    Series of compounds synthesized for preliminary evaluation through their 68Ga-labeled versions. Note presence of cold iodine in various strategic positions. EuK = glutamate–urea–lysine.

  • FIGURE 3.
    FIGURE 3.

    (A) Synthetic pathway toward key amino acid 9 (Fmoc-3TMS-Phe). (a) AcCl, methanol, 80°C, 5 h (i); Boc2O, Et3N, tetrahydrofuran, room temperature (r.t.), overnight (o.n.) (ii). (b) Pd2(dba)3, Me3Si2, water, KHCO3, meCgPPh, dimethylformamide, 100°C, 72 h. (c) LiOH, tetrahydrofuran/water, r.t., 1.5 h (i); 4 M HCl, dioxane, r.t., 30 min (ii). (d) Fmoc-Cl, 10% NaHCO3(aqueous)/dioxane, 0°C, 2 h. (B) Synthesis and subsequent radiolabeling of lead candidate precursors PSGa-3 and PSTMS-3. (e) Standard solid-phase peptide synthesis: hexafluorophosphate azabenzotriazole tetramethyl uronium, N,N-diisopropylethylamine, dimethylformamide, 35°C, 60 min to o.n. (i); 20% piperidine in dimethylformamide, 35°C, 10 min (ii); trifluoroacetic acid–water–triisopropylsilane (94:3:3), r.t., 2 h, or 4 M HCl, dioxane, r.t., 2 h (iii). (f) 68Ga3+, (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) (1.0 M, pH 4.0), 95°C, 5 min. (g) 211At, methanol, trifluoroacetic acid, 70°C, 10 min (i); 10 mM natGa(NO)3 in 0.1 M HCl, NaOAc buffer (pH 4.5), 70°C, 10 min (ii).

  • FIGURE 4.
    FIGURE 4.

    (A) PET/MRI maximum intensity projections 2 h after injection of 0.5 nmol of 68Ga-labeled surrogate compounds and reference PSMA-617. (B) Tumor-to-kidney ratios 2 h after injection. (C) Tumor accumulation (SUV) 0–60 min after injection in LNCaP nude mouse (BALB/c nu/nu) model (n = 1). B = bladder; K = kidney; T = tumor.

  • FIGURE 5.
    FIGURE 5.

    (A) Biodistribution (%ID/g) of [211At]PSAt-3-Ga in dissected organs (n = 4 for 2 h after injection; n = 6 for 6 and 24 h after injection). (B) Tumor-to-organ ratios (n = 4 for 2 h after injection; n = 6 for 6 and 24 h after injection). Detailed values in supplemental materials. p.i. = postinjection.

Tables

  • TABLE 1.

    In Vitro Characterization Data of 68Ga-Labeled Surrogate Compounds (n = 3)

    CompoundSpecific internalization (%AA/105 cells)*Ki (nM)†Lipophilicity‡Plasma protein binding (%)
    MouseHuman
    PSMA-6170.14 ± 0.0417.8 ± 5.9−3.5 ± 0.163.3 ± 2.476.7 ± 3.2
    PSGa-20.15 ± 0.0627.4 ± 3.0−3.4 ± 0.166.6 ± 0.576.4 ± 0.9
    PSGa-30.16 ± 0.0328.7 ± 4.4−3.8 ± 0.155.8 ± 2.367.5 ± 4.2
    PSGa-40.05 ± 0.0114.7 ± 4.6−3.7 ± 0.255.9 ± 0.970.5 ± 3.5
    PSGa-50.14 ± 0.0512.9 ± 1.8−3.6 ± 0.166.2 ± 4.771.8 ± 1.1
    PSGa-60.02 ± 0.0114.1 ± 3.8−2.5 ± 0.251.5 ± 1.565.6 ± 3.2
    PSGa-70.16 ± 0.0230.5 ± 8.9−2.1 ± 0.183.7 ± 1.087.3 ± 0.8
    PSGa-80.15 ± 0.0317.7 ± 2.2−3.0 ± 0.281.5 ± 1.296.7 ± 1.8
    PSGa-90.13 ± 0.0423.4 ± 3.7−2.9 ± 0.184.2 ± 1.194.0 ± 1.0

    • ↵* Specific internalization refers to total internalization (n = 3) corrected with blocked internalization in presence of 500 µM 2-phosphonomethyl pentanedioic acid, expressed as percentage applied activity (%AA) per 105 cells.

    • ↵† Inhibitor constant (Ki) is determined through Cheng–Prusoff method in competition assay (n = 3) with 0.75 nM [68Ga]Ga-PSMA-10 (Kd = 3.8 ± 1.8 nM).

    • ↵‡ Lipophilicity is logDoct/PBS.

    • oct = n-octanol; PBS = phosphate-buffered saline.

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