Investigating CNS distribution of PF-05212377, a P-glycoprotein substrate, by translation of 5-HT 6 receptor occupancy from non-human primates to humans.

PF-05212377 (SAM760) is a potent and selective 5-HT ₆ antagonist, previously under development for the treatment of Alzheimer's disease. In vitro, PF-05212377 was determined to be a P-gp/non-BCRP human transporter substrate. Species differences were observed in the in vivo brain penetration of PF-05212377 with a ratio of the unbound concentration in brain/unbound concentration in plasma (C _bu /C _pu ) of 0.05 in rat and 0.64 in non-human primates (NHP). Based on pre-clinical evidence, brain penetration and target engagement of PF-05212377 was confirmed in NHP using positron emission tomography (PET) measured 5-HT ₆ receptor occupancy (%RO). The NHP C _pu EC ₅₀ of PF-05212377 was 0.31 nM (consistent with the in vitro human 5HT6 K _i : 0.32 nM). P-gp has been reported to be expressed in higher abundance at the rat BBB and in similar abundance at the BBB of non-human primates and human; brain penetration of PF-05212377 in humans was postulated to be similar to that in non-human primates. In humans, PF-05212377 demonstrated dose and concentration dependent increases in 5-HT ₆ RO; maximal 5-HT6 RO of ∼80% was measured in humans at doses of ≥15 mg with an estimated unbound plasma EC ₅₀ of 0.37 nM (which was similar to the in vitro human 5HT6 binding K _i 0.32 nM). In conclusion, cumulative evidence from NHP and human PET RO assessments confirmed that NHP is more appropriate than the rat for the prediction of human brain penetration of PF-05212377, a P-gp/non-BCRP substrate. Clinical trial number: NCT01258751.
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