I have been running Ptolus since 2006 under multiple systems (3E, Castles & Crusades and 5E).
I think Shadowdark would handle the Dungeon aspects of the setting extremely well as well as the warring thieves guild intrigue. The big cosmic stuff available at high levels will be a lot harder to do -- the big endgame dungeon will be a nightmare to convert, for instance, especially since hacking one's way through it is a big part of what's required to save the world -- but that's really the only real problem I see.
Ptolus is one of the best urban fantasy RPG settings ever (arguably the best) and I think a campaign centered on Delvers Square in particular will work amazingly in Shadowdark.