OtherBasic Science Investigations

Evaluation of 5-11C-Methyl-A-85380 as an Imaging Agent for PET Investigations of Brain Nicotinic Acetylcholine Receptors

Yasuhiko Iida, Mikako Ogawa, Masashi Ueda, Akiko Tominaga, Hidekazu Kawashima, Yasuhiro Magata, Shingo Nishiyama, Hideo Tsukada, Takahiro Mukai and Hideo Saji
Journal of Nuclear Medicine May 2004, 45 (5) 878-884;

Article Figures & Data

Figures

  • FIGURE 1.
    FIGURE 1.

    Radiosynthesis of 11C-5MA. TFA = trifluoroacetic acid.

  • FIGURE 2.
    FIGURE 2.

    Inhibition of (−)-3H-cytisine binding to rat cortical membranes by various drugs.

  • FIGURE 3.
    FIGURE 3.

    Regional brain uptake of 11C-5MA in mice. •, Thalamus; ○, cortex; ▴, striatum; ▪, cerebellum. Data are presented as mean ± SD.

  • FIGURE 4.
    FIGURE 4.

    Correlation between radioactivity levels determined from in vivo distribution of 11C-5MA and density of nicotinic cholinergic receptor sites as determined by in vitro (−)-3H-cytisine binding (35).

  • FIGURE 5.
    FIGURE 5.

    Effect of various drugs on regional uptake of 11C-5MA in mice 30 min after injection. 11C-5MA was intravenously injected 5 min after intravenous administration of (−)-cytisine (1 mg/kg), (−)-nicotine (60 μg/kg), dexetimide (10 mg/kg), 5MA (0.1 mg/kg), and saline and 30 min after subcutaneous administration of scopolamine (10 mg/kg) and mecamylamine (5 mg/kg). Data are presented as mean ± SD. *P < 0.01 as compared with saline control group (Dunnett multiple comparisons test).

  • FIGURE 6.
    FIGURE 6.

    Transaxial PET images at 60–90 min after injection of 11C-5MA in rhesus monkey. (A) 11C-5MA alone. (B) (−)-Cytisine (5 mg/kg) administered 90 min before 11C-5MA injection.

  • FIGURE 7.
    FIGURE 7.

    Time-radioactivity curves of 11C-5MA in rhesus monkey. (−)-Cytisine (5.0 mg/kg) was intravenously administered 50 min after 11C-5MA injection. •, Thalamus in control study; ▪, cerebellum in control study; ○, thalamus in (−)-cytisine displacement study; □, cerebellum in (−)-cytisine displacement study.

Tables

  • TABLE 1

    Ki Values for Inhibiting (−)-3H-Cytisine Binding to Rat Brain Synaptosomal Membranes

    CompoundKi (nmol/L)
    5MA0.27 ± 0.16*
    A-853800.38 ± 0.01*
    (−)-Cytisine0.92 ± 0.42*
    (−)-Nicotine2.71 ± 0.73*
    Acetylcholine13.40 ± 2.61*
    Mecamylamine>1,000,000†
    α-Bungarotoxin>1,000,000†

    • ↵* Mean ± SD of 3 independent experiments.

    • ↵† Not inhibited at the highest concentration tested (10−4 mol/L).

  • TABLE 2

    Biodistribution of Radioactivity After Administration of 11C-5MA

    BiodistributionTime after injection (min)
    25153060
    Blood1.73 ± 0.351.35 ± 0.021.09 ± 0.060.83 ± 0.110.42 ± 0.02
    Intestine3.08 ± 0.583.22 ± 0.562.47 ± 0.132.44 ± 0.341.90 ± 0.39
    Liver7.29 ± 1.307.80 ± 0.365.53 ± 0.334.09 ± 0.522.34 ± 0.24
    Kidney20.0 ± 3.9918.2 ± 0.1921.6 ± 4.216.94 ± 1.094.88 ± 0.93
    Stomach2.01 ± 0.172.79 ± 0.342.56 ± 0.133.52 ± 0.522.19 ± 1.00
    Spleen3.31 ± 0.685.46 ± 0.974.28 ± 0.524.14 ± 1.831.57 ± 0.82
    Pancreas7.77 ± 1.087.00 ± 1.233.30 ± 0.121.93 ± 0.220.88 ± 0.24
    Heart4.87 ± 1.602.94 ± 0.511.53 ± 0.211.12 ± 0.300.62 ± 0.34
    Lung7.14 ± 2.465.78 ± 0.782.42 ± 0.461.54 ± 0.290.94 ± 0.32
    Brain1.23 ± 0.121.66 ± 0.092.24 ± 0.122.19 ± 0.241.87 ± 0.21
    Br/Bl*0.71 ± 0.151.23 ± 0.072.06 ± 0.192.65 ± 0.234.28 ± 0.46

    • ↵* Br/Bl = brain-to-blood ratio (percentage of injected 11C dose/gram of organ ratio).

    • Biodistribution of radioactivity is expressed as percentage of injected 11C dose/gram of organ (mean ± SD for 4 mice).

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