Article Figures & Data
Figures
- FIGURE 1.
Synthetic route for radiolabeling 11C-GSK215083.
- FIGURE 2.
Baseline PET images showing biodistribution of 11C-GSK215083 in pig (A), NHP (B), and human (C) brain (scale bar = %ID/L).
- FIGURE 3.
Representative baseline time–activity curves of 11C-GSK215083 in pig (A), NHP (B), and human (C) brain.
- FIGURE 4.
Blood metabolite profile of 11C-GSK215083 in pig and NHP (mean ± SEM).
- FIGURE 5.
Representative time–activity curves of 11C-GSK215083 before and after administration of blocking dose of unlabeled GSK215083 in pig (0.5 mg/kg) (A) and NHP (0.05 mg/kg) (B), for putamen (5-HT6-rich) and cerebellum (reasonably 5-HT6-devoid) regions of interest.
- FIGURE 6.
Plot of in vivo VT vs. log total mass dose of unlabeled GSK215083 (in vivo saturation plots) in pig (A) and NHP (B). Corrected Akaike criteria indicate that, in this primate species, cerebellum is best described by a constant and, in both species, all other regions are best described by a nonlinear saturation model.
Tables
Receptor Ki (nM) 5-HT6 0.16 5-HT2A 0.79 5-HT2B 9.1 5-HT2C 17.7 5-HT1D 70 5-HT1B 105 α1B-adrenoreceptor 977 Dopamine-D2 912 Dopamine-D3 977 5-HT1A >7,000 5-HT7 >10,000 Ki values were generated from competition studies performed on recombinant HeLa cell lines stably expressing human form of 5-HT6 receptor (23).
- TABLE 2
VT Values (mL/cm3) Generated for Individual Brain Regions from In Vivo Saturation Studies Conducted on Pigs and NHPs
Species Mass GSK215083 (μg) Putamen Caudate Frontal cortex Cerebellum Pig 2 16.5 14.9 11.7 8.6 200 11.8 11.4 9.4 8.0 2,000 10.9 10.8 8.7 7.7 20,000 9.4 9.4 7.5 6.9 NHP 0.76 24.30 22.01 17.55 14.34 6.66 20.93 19.52 18.90 17.96 13.61 20.67 18.30 17.29 16.44 72.40 15.72 14.04 13.31 11.55 1,176.30 20.09 17.94 14.10 16.78 11,751.00 16.32 14.62 10.74 13.68 - TABLE 3
Comparison of In Vitro Human Binding Affinities of GSK215083 with In Vivo Primate ED50 Values
Parameter 5-HT6 affinity (nM) 5-HT2A affinity (nM) 5-HT6 ED50 (μg) 5-HT2A ED50 (μg) Selectivity: 5-HT6 vs. 5-HT2A In vitro 0.16* 0.79* — — 4.94 In vivo — — 10.16 55.10 5.42 ↵* Values were taken from selectivity profile given in Table 1 (23).
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