Article Figures & Data
Figures
- FIGURE 1.
Radiosynthesis of 18F-MNI-444 from its tosylate precursor. DMSO = dimethyl sulfoxide.
- FIGURE 2.
Average 18F-MNI-444 PET images over 180 min for rhesus macaque in transverse plane at baseline and after dosing with tozadenant at 1.5 and 10.5 mg/kg (occupancy of 47% and 95%, respectively) or with preladenant at 0.004 and 0.2 mg/kg (occupancy of 32% and 90%, respectively). Monkey individual MR image is also shown. SUV = standardized uptake value.
- FIGURE 3.
(A) Representative time–activity curves at baseline for rhesus macaque in some brain regions after bolus injection of 18F-MNI-444. Dashed lines represent SRTM fit. (B) LGA with plasma input function. Dashed lines represent linear regression with t* set to 60 min. (C) NI-LGA with reference region input function. Dashed lines represent linear regression with t* set to 60 min and k′2 set to 0.35 min−1. △ = caudate; □ = putamen; ○ = globus pallidus; × = nucleus accumbens; ● = cerebellum.
- FIGURE 4.
Correlation of SRTM and NI-LGA BPND with LGA BPND for acquisitions of 120 min (A) or 180 min (B). ○ = SRTM; △ = NI-LGA; solid line = line of identity; dashed line = SRTM linear regression fit; dotted line = NI-LGA linear regression fit.
- FIGURE 5.
Time–activity curves for rhesus macaque in putamen (A) and cerebellum (B) after bolus injection of 18F-MNI-444 at baseline and after dosing with tozadenant or preladenant. ○ = baseline scan; ■ = tozadenant, 1.5 mg/kg; □ = preladenant, 0.004 mg/kg; ▲ = tozadenant, 10.5 mg/kg; △ = preladenant, 0.2 mg/kg.
- FIGURE 6.
Striatal A2A RO against preladenant (A) or tozadenant (B) administered doses, and against preladenant (C) or tozadenant (D) plasma levels at beginning of scan. Symbols represent occupancy estimates using LGA (○), SRTM (△), or NI-LGA (□) for 120 min of data. Lines represent model fits using LGA (solid line), SRTM (dashed line), or NI-LGA (dotted lines) occupancy estimates.
- FIGURE 7.
Pharmacokinetic modeling of tozadenant and preladenant plasma concentrations in humans was used to predict A2A RO after repeated dosing (180 mg BID of tozadenant and 10 mg BID of preladenant).
Tables
Region VT LGA BPND LGA BPND SRTM BPND NI-LGA Caudate 21.9 ± 3.0 5.5 ± 1.5 6.8 ± 1.0 6.3 ± 1.0 Putamen 30.3 ± 5.8 8.0 ± 2.7 9.6 ± 1.9 9.1 ± 2.0 Globus pallidus 16.1 ± 3.9 3.6 ± 0.7 4.5 ± 0.9 4.2 ± 0.9 Nucleus accumbens 12.4 ± 2.1 2.6 ± 0.4 3.5 ± 0.4 3.2 ± 0.3 Frontal cortex 4.7 ± 1.3 0.3 ± 0.1 0.2 ± 0.1 0.2 ± 0.1 Temporal cortex 3.5 ± 0.6 0.0 ± 0.0 0.0 ± 0.0 0.0 ± 0.0 Occipital cortex 3.6 ± 0.3 0.1 ± 0.1 0.1 ± 0.1 0.1 ± 0.1 Cerebellum 3.5 ± 0.7 NA NA NA NA = not applicable.
Data are mean ± SD (n = 6).
Occupancy (%) for 180 min of data Occupancy (%) for 120 min of data Drug Dose (mg/kg) LGA SRTM NI-LGA LGA SRTM NI-LGA Preladenant 1.0 103 100 101 102 100 101 0.2 90 92 91 92 93 92 0.04 69 76 73 73 78 76 0.015 39 45 42 45 49 45 0.015 53 56 55 52 58 56 0.010 35 44 40 43 49 45 0.004 32 26 27 32 27 27 0.004 23 25 25 29 26 27 Tozadenant 10.5 95 94 94 94 94 94 7.5 93 84 88 91 83 87 5.0 76 68 71 76 66 69 1.5 47 42 44 49 42 44 1.3 43 44 46 44 43 45 0.5 28 26 27 26 26 25
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