What is the most reliable and powerful 22 caliber pistol for defensive purposes made?

You're not really going to find any significant differences between .22 LR pistols. I do believe the Thompson Contender can be chambered in .22-250, and it's a very simple single shot mechanism... however, probably not really what you had in mind.

What kind of loads are you going to be putting through it? You really can't go wrong with a Ruger Mk. I/II/III, except that they can be a bit difficult taking apart and putting back together for cleaning. The Sig Mosquito is an Excellent pistol, but very fickle about which ammo it likes. Of course, a good revolver is always an Excellent choice for barrel length and reliability - but only from reputable manufacturers, such as Ruger, Smith & Wesson, etc.

However, I can't really recommend a .22 for self defence. Granted, shot placement makes all the difference, but still...