Table 1. Overview of PDEs’ Substrate Specificity, Localization in the CNS, Studied Inhibitors, and Relevant Literature References.

isoform	substrate	localization in CNS	inhibitors	references
PDE1	cAMP/cGMP	hippocampus, cortex, thalamus, striatum	vinpocetine, investigational synthetic PDE1 inhibitors	Shekarian et al.,52 Deshmukh et al.,51 Medina et al.,53 Li et al.,55 Snyder et al.,56 Dyck et al.57
PDE2	cAMP/cGMP	hippocampus, cortex, amygdala	BAY 6007550, ND-7001	Reneerkens et al.,58 Sierksma et al.,59 Gomez et al.60
PDE3	cAMP/cGMP	cerebellum, frontal cortex, hypothalamus, hippocampus	cilostazol	Yanai et al.,61 Hiramatsu et al.62 Arai et al.,63 Sakurai et al.,64 Tai et al.,65 Tai et al.66
PDE4	cAMP	hippocampus, cortex	rolipram, GSK356278, BPN14770, MEM 1414, MK-0952, HT-0712, roflumilast	García-Barroso et al.,1 Prickaerts et al.,3 García-Osta et al.,34 Ricciarelli et al.,71 Burgin et al.,72 Gallant et al.,73 Van Duinen et al.74
PDE6	cGMP	pineal gland	–	Argyrousi et al.86
PDE7	cAMP	hippocampus, cortex, olfactory bulb, striatum, thalamus, hypothalamus, midbrain	investigational synthetic PDE7 inhibitors	Morales-Garcia et al.,78 Argyrousi et al.86
PDE8	cAMP	hippocampus, cortex, olfactory bulb, striatum, thalamus, hypothalamus, midbrain	PF-04957325	Pérez-Torres et al.,79 Vang et al.,80 Argyrousi et al.86
PDE9	cGMP	hippocampus, cortex, olfactory bulb, striatum, thalamus, hypothalamus, amygdala, midbrain, cerebellum	PF-04447943, BI 409306, BAY 73-6691	Schwam et al.,81 Moschetti et al.,82 Li et al.,83 Argyrousi et al.86
PDE10	cAMP/cGMP	striatum	–	Argyrousi et al.86
PDE11	cAMP/cGMP	low expression levels throughout the brain	–	Argyrousi et al.86