[Suicide Junkie]

Grab the TDM AIs for a great unmodded game challenge.

Other things you can do include cranking up the AI bonus, playing simultaneous turn mode and restricting yourself from using the most advantageous tactics.
Taking over for a neutral empire while leaving your original empire to be run by the AI will be very challenging (Your ships can't use the warppoints!)

Limiting yourself to colonizing a small number of systems (say 2) also makes for an interesting economic and tactical challenge.