Research ArticleBasic Science Investigations

In Vivo Biodistribution of No-Carrier-Added 6-18F-Fluoro-3,4-Dihydroxy-l-Phenylalanine (18F-DOPA), Produced by a New Nucleophilic Substitution Approach, Compared with Carrier-Added 18F-DOPA, Prepared by Conventional Electrophilic Substitution

Willem-Jan Kuik, Ido P. Kema, Adrienne H. Brouwers, Rolf Zijlma, Kiel D. Neumann, Rudi A.J.O. Dierckx, Stephen G. DiMagno and Philip H. Elsinga
Journal of Nuclear Medicine January 2015, 56 (1) 106-112; DOI: https://doi.org/10.2967/jnumed.114.145730

Article Figures & Data

Figures

  • FIGURE 1.
    FIGURE 1.

    Two-step synthesis of 18F-DOPA from precursor ALPDOPA, ((S)-methyl-3-(4,5-bis(ethoxymethoxy)2-iodophenyl)-2-(di-(tert-butoxycarbonyl))amino)propanoate)(4-methoxyphenyl)-λ3-iodane trifluoromethanesulfonate. Radiochemical yield, 14% ± 4% EOB; enantiomeric excess > 99%.

  • FIGURE 2.
    FIGURE 2.

    (A) Influence of temperature on uptake of 18F-DOPA by BON-1 cells (n = 5–6 for 0°C and 10–11 for 37°C). *P ≤ 0.05, 0°C: 18F-DOPA-H vs. 18F-DOPA-L; #P ≤ 0.05, 18F-DOPA-H: 0°C vs. 37°C; ##P ≤ 0.05, 18F-DOPA-L: 0°C vs. 37°C. (B) Influence of inhibition of LAT in BON-1 cells by 1 mM BCH (n = 10–11 for control and 4 for BCH-treated). #P ≤ 0.05, 18F-DOPA-H: control vs. BCH; ##P ≤ 0.05, 18F-DOPA-L; control vs. BCH. (C) Influence of inhibition of AADC in BON-1 cells by 0.08 mM carbidopa (n = 10–11 for control and 5 for carbidopa-treated). *P ≤ 0.05, carbidopa: 18F-DOPA-H vs. 18F-DOPA-L; #P ≤ 0.05, 18F-DOPA-L; control vs. carbidopa. (D) Influence of inhibition of MAO in BON-1 cells by 0.1 mM pargyline (n = 10–11 for control and 4–5 for pargyline-treated). *P ≤ 0.05, pargyline: 18F-DOPA-H vs. 18F-DOPA-L; #P ≤ 0.05, 18F-DOPA-L: control vs. pargyline. (E) Influence of inhibition of VMAT in BON-1 cells by 0.01 mM tetrabenazine (TBZ; n = 10–11 for control and 3–4 for TBZ-treated). *P ≤ 0.05, TBZ: 18F-DOPA-H vs. 18F-DOPA-L; #P ≤ 0.05, 18F-DOPA-H: control vs. TBZ; ##P ≤ 0.05, 18F-DOPA-L: control vs. TBZ.

  • FIGURE 3.
    FIGURE 3.

    (A) Coronal sections, reconstructed from summed time frames of 30–90 min, of athymic nude mice. Intensity of signal reflects standardized uptake values (SUVs) as indicated on bar on right. Locations with relatively high uptake are indicated by white arrows: tumor xenograft on right shoulder (T), pancreas (P), and urinary bladder (U). (B) Time–activity curves of 18F-DOPA with mean SUVs determined from regions of interest drawn at location of BON-1 tumor xenograft in PET images. *P ≤ 0.05, 18F-DOPA-H; no carbidopa vs. carbidopa.

  • FIGURE 4.
    FIGURE 4.

    (A) Biodistribution of 18F-DOPA in mice bearing BON-1 tumor xenograft at 105 min after tracer injection. *P ≤ 0.05, 18F-DOPA-H: no carbidopa vs. carbidopa. (B) Ratio of standardized uptake values (SUVs) of tumor vs. several reference tissues, based on SUV determined by biodistribution experiment. *P ≤ 0.05, 18F-DOPA-H: no carbidopa vs. carbidopa.

  • FIGURE 5.
    FIGURE 5.

    Fraction of radiometabolite 6-18F-fluorodopamine contributing to whole amount of radioactivity of applied radio-TLC sample. *P ≤ 0.05, 18F-DOPA-H: no carbidopa vs. carbidopa.

  • FIGURE 6.
    FIGURE 6.

    Overview cellular uptake mechanism of 18F-DOPA. 18F-DOPA is taken up by LAT in exchange for other neutral amino acids (e.g., leucine). Enzyme AADC metabolizes 18F-DOPA to 6-18F-fluorodopamine, which in turn can be either sequestered in secretory vesicles by VMAT or degraded by other enzymes, such as MAO, to break down products that are rapidly cleared from the cell.

Tables

  • TABLE 1

    Characteristics of Experimental Animals

    Experimental group18F-DOPA-L, carbidopa18F-DOPA-H, no carbidopa18F-DOPA-H, carbidopa
    No. of animals444
    20 μg of (S)-carbidopa pretreatmentYesNoYes
    Specific activity (GBq/mmol)*61.1 ± 26.0, low45,355 ± 1,565, high24,750 ± 1,246, high
    Amount of 18F-DOPA (pmol/g)*228.3 ± 5.70.33 ± 0.030.64 ± 0.15
    Body weight (g) at tumor inoculation*20.6 ± 0.223.1 ± 0.423.4 ± 1.0
    Body weight (g) at small-animal PET experiment*19.8 ± 0.422.0 ± 0.722.0 ± 0.8
    Weight loss (%)*3.9 ± 2.64.5 ± 1.75.8 ± 1.7
    Weight of excised tumor (mg)*284 ± 105309 ± 44335 ± 79
    Plasma protein binding (%)*24.0 ± 2.522.5 ± 2.220.7 ± 2.7

    • ↵* Values represent mean ± SE.

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