Article Figures & Data
Figures
- FIGURE 1.
Radiosynthesis of 18F-JNJ-64413739.
- FIGURE 2.
Rat intravenous pharmacokinetics profile: time vs. plasma concentration of JNJ-64413739 (n = 3).
- FIGURE 3.
Brain vs. plasma concentration of JNJ-64413739 in rats (n = 3) over time.
- FIGURE 4.
Microdosing blocking of retention of JNJ-64413739 in rat brain pretreated with JNJ-55308942 or vehicle (n = 3 each). *P < 0.01 vs. control.
- FIGURE 5.
Brain uptake/retention of JNJ-64413739 in wild-type and KO mice (n = 4 each). *P < 0.05 vs. wild-type.
- FIGURE 6.
18F-JNJ-64413739 NHP PET: blocking with P2X7 inhibitor JNJ-54175446. Summed images at 30–120 min normalized to SUV acquired after either vehicle or JNJ-54175446 at different dose levels are shown for monkey 1 (A) and monkey 2 (C). Corresponding time–activity curves of thalamus expressed as SUV are shown for monkey 1 (B) and monkey 2 (D). JNJ-739 = JNJ-64413739; JNJ-446 = JNJ-54175446.
Tables
Assay JNJ-64413739 IC50 P2X7 human (nM) 1.0 ± 0.2 IC50 P2X7 rat (nM) 2.0 ± 0.6 Ki P2X7 human (nM) 15.9 ± 2.0 Ki P2X7 rat (nM) 2.7 ± 1.1 IC50 = half-maximal inhibitory concentration; Ki = binding affinity.
Rat no. CL (mL/min/kg) CL (L/h/kg) Vd (L/kg) Vss (L/kg) AUCINF (h*ng/mL) C0 (ng/mL) C0 (μM) Half-life, terminal (h) 4 33.6 2.0 1.6 1.3 497 1660 4.1 0.6 5 34.8 2.1 1.5 1.3 479 2119 5.2 0.5 6 41.6 2.5 1.8 1.6 401 921 2.3 0.5 Mean 36.6 2.2 1.7 1.4 459 1567 3.8 0.5 SD 4.3 0.3 0.2 0.1 51 604 1.5 0.0 %CV 12 12 9 11 11 39 39 5 CL = clearance; Vd = volume of distribution; Vss = apparent volume of distribution at steady state; AUCINF = area under the curve extrapolated to infinite time; C0 = extrapolated plasma concentration at time 0; %CV = percentage coefficient of variation.
Dose (mg/kg) AUC (ng/mL × min) Receptor occupancy (%) Monkey 5.3 132470 51.7 2 2.5 46991 60.4 1 2.5 42353 55.1 2 0.4 5764 52.1 2 0.1 2102 17.6 1 AUC = area under the curve.
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