L-745870 hydrochloride has excellent brain penetration. L-745870 hydrochloride is a high-affinity, selective and orally active human dopamine D4 receptor antagonist with a Ki of 0.43 nM, and considerably weaker D2 receptor affinity with a Ki of 960 nM and D3 receptor affinity with a Ki of 2300 nM. 

D3 receptor (human):2300 nM(Ki), D4 receptor (human):0.43 nM(Ki), D2 receptor (human):960 nM(Ki)

In vitro pharmacological studies revealed that L-745870 is an antagonist at human D4 receptors, in that L-745870 antagonized the ability of D4 receptors to inhibit agonist-induced stimulation of [35S]-GTPgS binding,?blocked the inhibition of forskolin-stimulated adenylate cyclase activity in transfected human embryonic kidney (HEK293) and Chinese hamster ovary (CHO) cells,?blocked dopamine-induced inhibition of Ca2+ currents in transfected GH4C1 pituitary cells,?inhibited D4 activation of cloned G protein-coupled inwardly rectifying K+ channels,?and antagonized dopamine-induced stimulation of extracellular acidification in transfected cells[1].

L-745870 exhibits favorable pharmacokinetic properties (20-60% oral bioavailability and plasma t1/2 of 2.1-2.8 hours) in both rats and monkeys, with excellent brain penetration and high brain-to-plasma ratios in rats[1]. Evaluation of L-745870 in surrogate marker assays indicates that it is readily available for biological activity in the brain and at doses of 5 to 60 mg/kg p.o., it would occupy 50% of D4 receptors in the brain. L-745870 does not affect apomorphine-induced stereotypy in rats but induces catalepsy in mice at a high dose of 100 mg/kg p.o., likely due to D2 receptor occupancy. Higher doses of L-745870 are anticipated to cause extrapyramidal symptoms in primates as these CNS levels would antagonize D2 receptors. In squirrel monkeys, L-745870 (10 mg/kg p.o.) induces mild sedation and at 30 mg/kg, it causes noticeable extrapyramidal motor symptoms, notably bradykinesia[1].