Phosphodiesterase 10A (PDE10A) is a nove
l target for the treatment of schizophrenia that may address mu
ltip
le symptomatic domains associated with this disorder. PDE10A is high
ly expressed in the brain and functions to metabo
lica
lly inactivate the important second messengers cAMP and cGMP. Here we describe effects of a potent and ora
lly bioavai
lab
le PDE10A inhibitor [2-(6-ch
loropyridin-3-y
l)-4-(2-methoxyethoxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-y
l](imidazo[1,5-a]pyridin-1-y
l)methanone] (THPP-1) on striata
l signa
ling pathways, in behaviora
l tests that predict antipsychotic potentia
l, and assays that measure episodic-
like memory in rat and executive function in rhesus monkey. THPP-1 exhibits nanomo
lar potency on the PDE10A enzyme, demonstrates exce
llent pharmacokinetic properties in mu
ltip
le prec
linica
l anima
l species, and is se
lective for PDE10A over other PDE fami
lies of enzymes. THPP-1 significant
ly increased phosphory
lation of proteins in the striatum invo
lved in synaptic p
lasticity, inc
luding the a-amino-3-hydroxy-5-methy
lisoxazo
le-4-proprionic acid receptor (AMPA) G
luR1 subunit, extrace
llu
lar receptor kinase (ERK), and cAMP-response e
lement binding protein (CREB). THPP-1 produced dose-dependent effects in prec
linica
l assays predictive of antipsychotic activity inc
luding attenuation of MK-801-induced psychomotor activation and condition avoidance responding in rats. At simi
lar p
lasma exposures, THPP-1 significant
ly increased object recognition memory in rat and attenuated a ketamine-induced deficit in the object retrieva
l detour task in rhesus monkey. These findings suggest that PDE10A inhibitors have the potentia
l to impact mu
ltip
le symptomatic domains of schizophrenia inc
luding positive symptoms and cognitive impairment.
This article is part of a Special Issue entitled ¡®Cognitive Enhancers¡¯.