TrkB agonist-1

5XFAD transgenic mice (bred in a pathogen-free environment, starting treatment at 2 months of age)^[1]

7.25 mg/kg/d; 21.8 mg/kg/d; 43.6 mg/kg/d

p.o.; daily; 3 months

Increased TrkB phosphorylation levels in a dose-dependent manner, with phosphorylated AKT and phosphorylated ERK downstream of TrkB also elevated in a dose-dependent manner.
Reversed pathological reduction of hippocampal CA1 region synaptic density in a dose-dependent manner, and increased long-term potentiation in a dose-dependent fashion.
Reduced Aβ deposition in both hippocampus and frontal cortex in a dose-dependent manner, and reduced brain Aβ40 concentrations at all tested doses.
Attenuated spatial memory acquisition deficit measured by Morris water maze latency AUC and swim path distance AUC, and significantly improved spatial memory recall in the probe trial.
Reduced mature active AEP enzymatic activity at 21.8 mg/kg and 43.6 mg/kg doses, and inhibited AEP-mediated pathological cleavage of APP and Tau.
Significantly reduced brain concentrations of the proinflammatory cytokines IL-1β, IL-6, and TNFα across all tested doses.

Male CD1 mice^[1]

21.8 mg/kg; 43.6 mg/kg; 72.5 mg/kg

p.o.; single dose

Reached mean plasma 7,8-DHF concentrations of 2.1 ng/mL at 21.8 mg/kg, 4.8 ng/mL at 43.6 mg/kg, and 6.9 ng/mL at 72.5 mg/kg at 4 hours post-administration.
Reached mean brain 7,8-DHF concentration of 3.4 ng/g at 4 hours post-administration for the 72.5 mg/kg dose.
Detected the intermediate T1 in plasma at mean concentrations of 10.2 ng/mL (21.8 mg/kg), 34.0 ng/mL (43.6 mg/kg), and 42.3 ng/mL (72.5 mg/kg), with T1 undetectable in brain across all doses.

Mice^[1]

36 mg/kg; 72.5 mg/kg

p.o.; single dose

Achieved mean Cmax of released 7,8-DHF of 129 ng/mL, Tmax of 30 min, AUC (0-t) value of 11880 min·ng/mL, and 7,8-DHF T1/2 of 219.6 min after a single 36 mg/kg oral dose, resulting in 10.5% oral bioavailability for R13.
Reached mean Cmax of 7,8-DHF in plasma of 56 ng/mL at 2 hours post-dose, and mean Cmax in brain tissue of 46 ng/g at 4 hours post-dose after a single 72.5 mg/kg oral dose, with 7,8-DHF concentrations remaining above 5 ng/g in brain for at least 240 minutes and 7,8-DHF still detectable in plasma at 8 hours after administration.