Research ArticleBasic Science Investigations

In Vivo Evaluation of 18F-SiFAlin–Modified TATE: A Potential Challenge for 68Ga-DOTATATE, the Clinical Gold Standard for Somatostatin Receptor Imaging with PET

Sabrina Niedermoser, Joshua Chin, Carmen Wängler, Alexey Kostikov, Vadim Bernard-Gauthier, Nils Vogler, Jean-Paul Soucy, Alexander J. McEwan, Ralf Schirrmacher and Björn Wängler
Journal of Nuclear Medicine July 2015, 56 (7) 1100-1105; DOI: https://doi.org/10.2967/jnumed.114.149583

Article Figures & Data

Figures

  • FIGURE 1.
    FIGURE 1.

    Structures of building blocks SiFA and SiFAlin.

  • FIGURE 2.
    FIGURE 2.

    Structures of 68Ga-DOTATATE, 18F-SiFAlin analogs (X = site of introduction of hydrophilic auxiliaries for optimizing in vivo biodistribution properties), and 18F-trifluoroborate derivative 18F-AMBF3-TATE.

  • FIGURE 3.
    FIGURE 3.

    Small-animal PET images of 3 generations of SiFA-derivatized somatostatin analogs evaluated in AR42J tumor–bearing rodents. All images show coronal slices of the 50–90 min postinjection time frame. (A) 18F-SiFA-TATE (18F-1) in vivo images were obtained using a Philips Mosaic small-animal PET scanner. (B) 18F-SiFA-Glc-PEG1-TATE (18F-3) images were obtained with a Siemens Inveon small-animal PET-scanner. (C) Images of 18F-SiFAlin-Glc-Asp2-PEG1-TATE (18F-9) distribution were obtained using a Bruker Albira small-animal PET/SPECT/CT scanner, indicating both a renal clearance and high activity accumulation in the SSTR-positive tumor tissue.

  • FIGURE 4.
    FIGURE 4.

    High tolerance of SSTR binding affinities of Tyr3-octreotate toward hydrophilic chemical modifications without loss of bioactive potency. Binding affinities of third-generation SiFA (green, PEG1: 4 and PEG5: 7) and SiFAlin (blue, PEG1: 9 and PEG5: 12) derivatives compared with second-generation (magenta, 3) were determined by competitive receptor binding affinity studies using AR42J cells and 177Lu-DOTATATE as competitor. After incubation for 60 min in buffer at ambient temperature and successive washing steps, both cell-bound and internalized activity were measured using a γ counter. All experiments were performed in triplicate (error bars, mean ± SD).

  • FIGURE 5.
    FIGURE 5.

    Results from ex vivo biodistribution studies comparing 68Ga-DOTATATE (n = 5) with 18F-9 (n = 10) in AR42J tumor–bearing mice at 60 min after injection. Values are given as %ID/g. Most promising 18F-SiFAlin-derivatized derivative 18F-9 demonstrates highly specific and even slightly higher tumor uptake than gold standard 68Ga-DOTATATE. For 18F-9, a blocking experiment using DOTATATE (200 μg/mouse; n = 5) was performed (dashed blue columns), showing specific binding of tracer to tumor and physiologically SSTR-positive tissues. 18F-SiFAlin derivatives enable tumor-to-background ratios comparable to 68Ga-DOTATATE.

  • FIGURE 6.
    FIGURE 6.

    Comparative small-animal PET/CT imaging of SSTR-positive tumor-bearing mice using 68Ga-DOTATATE (A) and 18F-9 (B) with identical standardized uptake value (SUV) scale for both images. Tumor accumulation SUVs in last frame (80–90 min after injection; showing highest accumulation of both tracers) are 5.50 for 68Ga-DOTATATE and 7.80 for 18F-9.

Tables

  • TABLE 1

    Tumor-to-Blood and Tumor-to-Muscle Ratios for Tested Newly Developed 18F-Labeled Peptides 18F-4, 18F-7, 18F-9, and 18F-12 Obtained from Ex Vivo Biodistribution at 90 Minutes after Injection

    Ratio18F-418F-918F-718F-12
    Tumor to blood4.30 ± 0.2657.58 ± 35.8912.31 ± 4.1974.42 ± 20.37
    Tumor to muscle33.31 ± 11.94211.05 ± 143.3894.12 ± 26.37256.49 ± 61.17

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