Research ArticleBasic Science Investigations

A PET Tracer for Renal Organic Cation Transporters, 11C-Metformin: Radiosynthesis and Preclinical Proof-of-Concept Studies

Steen Jakobsen, Morten Busk, Jonas Brorson Jensen, Ole Lajord Munk, Nora Elisabeth Zois, Aage K.O. Alstrup, Niels Jessen and Jørgen Frøkiær
Journal of Nuclear Medicine April 2016, 57 (4) 615-621; DOI: https://doi.org/10.2967/jnumed.115.169292

Article Figures & Data

Figures

  • FIGURE 1.
    FIGURE 1.

    Synthesis scheme for 11C-metformin.

  • FIGURE 2.
    FIGURE 2.

    11C-metformin uptake in OCT1- and OCT2-expressing LLC-PK1 cells (A) at baseline (●) and with increasing concentrations of unlabeled metformin, 2.5 mM (▪) and 10 mM (▲) (all; n = 3). (B) 11C-metformin release kinetics in previously tracer-loaded cells after reincubation in tracer-free medium.

  • FIGURE 3.
    FIGURE 3.

    Autoradiography of rat liver (A) and kidney (B) were obtained 2 min after injection of 11C-metformin. There is augmented uptake of 11C-metformin in kidney compared with liver, and kidney distribution of 11C-metformin demonstrates that accumulation is most intensive in renal medulla. *A cutting artifact. Max = maximum; min = minimum.

  • FIGURE 4.
    FIGURE 4.

    Pharmacokinetics and drug interaction of 11C-metformin studies in rats subjected to PET. (A) Summed parametric images (I–IV) and corresponding CT image (V). (B and C) Representative regional time–activity curves (B) after injection of 11C-metformin show rapid cortical uptake and subsequent accumulation in renal medulla and pelvis, which yields 90-min summed parametric image shown in C. (D and E) Examples of drug-induced changes in renal cortex time–activity curves (D) and corresponding whole kidney (solid color) and liver (shaded color) SUVs in rats examined at baseline and after metformin, TBA, cimetidine, cisplatin, and quinine (all; n = 3) (E).

  • FIGURE 5.
    FIGURE 5.

    Time–activity curves for renal cortex, liver, and blood at baseline (black) and after pretreatment with cold metformin (red). Top panels show 11C-metformin radioactivity in central coronal plane containing both kidneys at selected times.

  • FIGURE 6.
    FIGURE 6.

    Whole-body pig biodistribution of 11C-metformin.

Tables

  • TABLE 1

    Summary of Pigs Used

    Pig no.Scan typePurposeBiologic sample evaluation
    1Whole-body baseline + postmetforminBiodistribution + dosimetryPlasma + urine metabolite
    2Dynamic PET/CT baselinePharmacokineticPlasma metabolite
    3Dynamic PET/CT baselinePharmacokineticPlasma metabolite
    4Dynamic PET/CT baseline + postmetforminPharmacokineticPlasma metabolite
    5Bolus + constant infusionRenal clearancePlasma protein binding, plasma + urine metabolite
    6Bolus + constant infusionRenal clearancePlasma protein binding, plasma + urine metabolite
  • TABLE 2

    Pharmacokinetics of 11C-Metformin Before and After Competition with Unlabeled Metformin

    ParameterBaselineUnlabeled metformin
    K1 (mL/mL/min)1.540.67
    k2 (min−1)0.220.15
    Vd (mL per mL of plasma)*74.5
    AUCcortex/AUCplasma†6.43.9
    Cl(plasma — > urin) (mL/min)‡382179

    • ↵* Distribution volume Vd = K1/k2.

    • ↵† AUCcortex/AUCplasma determined at presumed steady state at 60 min after injection.

    • ↵‡ Urinary clearance Cl = k2 × Vcortex × AUCcortex/AUCplasma; with Vcortex = 2 × 115 mL.

    • AUC = area under the curve.

  • TABLE 3

    Urine Clearance of 11C-Metformin, 51Cr-EDTA, Protein Binding, and Metabolites in Plasma from 2 Pigs

    ParameterPig no. 5Pig no. 6
    ClMET (mL/min)348, 388334
    ClEDTA (mL/min)114, 11791
    ClMET/ClEDTA3.05, 3.323.67
    Protein binding (%)<0.5<0.5
    MetabolitesNoneNone

    • ClMET = urine clearance of 11C-metformin; ClEDTA = urine clearance of 51Cr-EDTA = glomerular filtration rate.

    • Pigs underwent constant infusion clearance technique experiments.

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