Article Figures & Data
Figures
- FIGURE 1.
Representative SV2A ligands and corresponding human SV2A pIC50 (11) compared with levetiracetam (LEV) pIC50 (19). pIC50 is the negative log of the IC50 value in molar units. pIC50 = −log10(IC50), where IC50 is half maximal inhibitory concentration. *Radiolabeling site.
- FIGURE 2.
Synthesis of UCB-J, 11C-UCB-J, and the radiolabeling precursor: a. KI, NaH, THF, 50°C; b. NaH, THF, 50°C; c. Bis(neopentyl glycolato)diboron, Pd(dppf)Cl2, AcOK, dioxane, 110°C; d. KHF2, r.t.; e. Pd2(dba)3/(o-tolyl)3P, K2CO3, DMF/H2O, 100°C, 5 min.
- FIGURE 3.
Metabolic pathways in rat plasma after single intravenous dose of UCB-J (1 mg/kg).
- FIGURE 4.
Representative SUV images summed from 30 to 45 min after 11C-UCB-J injections: baseline (A), after pretreatment with levetiracetam (10 mg/kg) (B), and after coinjection with unlabeled UCB-J (150 μg/kg) (C).
- FIGURE 5.
Time–activity curves in selected brain regions from 11C-UCB-J baseline (A) and blocking (B) scans after pretreatment with levetiracetam (10 mg/kg).
- FIGURE 6.
Bar graph representation of 11C-UCB-J self-blocking scans after coadministration of UCB-J (17, 50, and 150 μg/kg).
- FIGURE 7.
In vivo Kd estimate for UCB-J from 1T VT values. Avg = average.
Tables
Study type Duration Route of administration Dose or concentration Studies in rats Preliminary pharmacokinetics Single dose Intravenous 1 mg/kg Distribution (brain exposure) Single dose Intravenous 0.1 mg/kg Distribution and metabolism in plasma and brain Single dose Intravenous 1 mg/kg In vitro studies Brain and plasma protein binding (interspecies) 1 μM In vitro permeation through the caco-2 cell model 2 μM Intrinsic clearance in microsomes (interspecies) 1 μM (rhesus), 5 μM (mouse, rat, and human) Metabolism in microsomes (interspecies) 1 μM Target H1 α2A α1A M2 δ1 κOR D2 5-HT1A 5-HT2A % inhibition 3 7 −4 2 4 3 2 −2 3 ↵* Performed in duplicate at concentrations of 10 μm.
- TABLE 4
Regional Binding Parameters for 11C-UCB-J at Baseline and After Preblocking with Levetiracetam
Preblocking VT with dose of levetiracetam* Brain region Baseline VT (n = 5) 10 mg/kg (n = 2) 30 mg/kg (n = 1) Bmax† (nmol/L) Amygdala 23.42 (1.3) 11.89 (0.5) 7.25 128 Brain stem 22.90 (2.0) 11.83 (0.3) 8.98 124 Caudate 43.39 (4.0) 19.71 (0.2) 11.53 276 Cerebellum 34.80 (3.8) 15.85 (0.9) 10.59 212 Cingulate cortex 53.41 (7.7) 22.68 (0.6) 12.79 350 Frontal cortex 52.96 (6.5) 21.32 (0.3) 11.49 347 Globus pallidus 27.13 (2.0) 16.01 (0.6) 11.3 155 Insula 52.45 (5.2) 22.47 (0.3) 12.97 343 Nucleus accumbens 51.63 (6.5) 24.12 (1.2) 13.39 337 Occipital cortex 50.85 (5.0) 20.14 (0.1) 11.8 331 Pons 22.78 (2.3) 11.50 (0.7) 9.3 123 Putamen 43.95 (1.9) 20.40 (1.0) 12.39 280 Substantia nigra 23.98 (2.2) 12.60 (0.2) 9.28 132 Temporal cortex 48.31 (4.9) 20.35 (0.2) 11.88 313 Thalamus 38.62 (4.8) 18.56 (1.9) 11.09 241 - TABLE 5
Mean Organ Radiation Dose (mGy/MBq) Estimates from 11C-UCB-J in 70-Kilogram Adult Male and 55-Kilogram Female Phantoms
Male Female Target organ Mean SD Mean SD Adrenals 1.75E–03 5.73E–04 1.46E–03 2.29E–05 Brain 1.74E–02 4.00E–04 1.81E–02 6.89E–04 Breasts 4.27E–04 1.22E–04 3.14E–04 7.65E–06 Gallbladder wall 3.24E–03 1.45E–03 3.68E–03 9.57E–05 Lower large intestine wall 7.11E–03 2.64E–03 6.68E–03 8.59E–04 Small intestine 6.27E–04 1.22E–04 6.30E–04 3.24E–05 Stomach wall 1.14E–03 2.41E–04 1.00E–03 7.08E–05 Upper large intestine wall 7.59E–04 2.50E–04 7.00E–04 2.10E–05 Heart wall 2.29E–03 6.95E–04 1.64E–03 7.46E–05 Kidneys 1.26E–02 2.60E–03 1.17E–02 5.92E–04 Liver 1.99E–02 9.49E–03 1.69E–02 1.91E–04 Lungs 5.24E–03 1.91E–05 3.00E–03 3.05E–04 Muscle 4.46E–04 1.13E–04 4.05E–04 5.73E–06 Ovaries ― ― 6.43E–04 7.65E–05 Pancreas 1.97E–03 5.16E–04 1.54E–03 4.00E–04 Red marrow 7.05E–04 1.16E–04 6.62E–04 3.81E–06 Osteogenic cells 6.62E–04 8.22E–05 6.89E–04 1.34E–05 Skin 3.11E–04 6.16E–05 2.89E–04 1.91E–06 Spleen 3.46E–03 4.78E–04 3.59E–03 1.29E–03 Testes 9.59E–05 2.45E–05 ― ― Thymus 4.76E–04 1.13E–04 3.41E–04 1.34E–05 Thyroid 4.11E–04 1.15E–05 2.20E–04 8.59E–06 Urinary bladder wall 3.24E–03 2.27E–03 9.38E–03 2.01E–03 Uterus ― ― 6.22E–04 8.97E–05 Total body 1.44E–03 3.27E–04 1.34E–03 1.34E–05 EDE 4.59E–03 3.43E–04 4.46E–03 9.57E–05 Effective dose 3.32E–03 1.53E–04 3.35E–03 1.72E–04
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