Animal experiment:

Tissue distribution studies with VU6005649 (compound 9f) in mice are performed by formulating VU6005649 in 10% polysorbate 80 and dosing via intraperitoneal injection to 20 week old female C57/Bl6 mice (3 per time point). At 0.25, 0.5, 1, 3, and 6 hours post dose, animals are euthanized and decapitated, blood is collected via cardiac puncture and the brains are removed, thoroughly washed in cold phosphate-buffered saline, and immediately frozen on dry ice[1].

VU6005649 is a CNS penetrant mGlu7/8 receptor agonist with EC50s of 0.65 uM and 2.6 uM for mGlu7 receptor and mGlu8 receptor, respectively.

VU6005649 is a CNS penetrant mGlu7/8 receptor agonist with EC50s of 0.65 uM and 2.6 uM for mGlu7 receptor and mGlu8 receptor, respectively. VU6005649 displays a terminal Kp of 2.43 with total brain levels ~9× above the mGlu7 positive allosteric modulator (PAM) in vitro EC50[1].

When VU6005649 (compound 9f) is dosed at 30 mg/kg IP in 10% Tween 80/H2O (0.75 mg/kg. s.c. amphetamine), no efficacy is observed in this assay. VU6005649 shows modest but significant pro-cognitive effects on associative learning in wild-type mice and the first example of efficacy of an mGlu7/8 positive allosteric modulator (PAM) in this model[1].

References:
[1]. Abe M, et al. Discovery of VU6005649, a CNS Penetrant mGlu7/8 Receptor PAM Derived from a Series of Pyrazolo[1,5-a]pyrimidines. ACS Med Chem Lett. 2017 Sep 1;8(10):1110-1115.