A series of analogues were synthesized by optimizing the structure of papaverine. The in vitro PDE10A binding affinity (IC 50) values for these new analogues were measured; for compounds that have IC 50 value less than 60 nM for PDE10A, the binding affinities (IC 50 value) for PDE3A and PDE3B were tested. Of these analogues, compounds 6a, 6b, 6n, 8b, 8c and 11 displayed relatively higher PDE10A potency with IC 50 value in the range of 28-60 nM. The most potent compound 1-(4-(2-(2-fluoroethoxy)ethoxy)- 3-methoxybenzyl)-6,7-dimethoxyisoquinoline (8c) has the IC 50 value of 28 ± 1.2 nM for PDE10A, 2200 ± 437 nM for PDE3A and 2520 ± 210 nM for PDE3B. Compared to papaverine, compound 8c displayed similar PDE10A potency but improved selectivity to PDE10A versus PDE3A and PDE3B. To identify high potent PDE10A inhibitor, further optimization of the structures of these analogues is necessary.