I think a good director/story teller could put in another Decepticon leader and pull it off. Michael Bay was willing to use really obscure characters as the main villains in ROTF and DOTM -- as others have mentioned, Megatron was like a 'sidekick' to The Fallen and Sentinel Prime in those films, and they were both fairly obscure characters before the films came along (although Sentinel Prime had became more prominent after Transformers Animated).
So long as you make the character really awesome, audiences will be drawn. Look at the Dark Knight Rises -- Bane isn't the most well known of Batman villains, no where near as well known to the general public as say the Joker, the Riddler, Penguin or even Dr. Freeze etc., but Nolan put him in his 3rd Batman film - and the movie was freaking awesome! Even Batman Begins used lesser known villains - i.e. Scarecrow and Ra's Al Ghul (whose story intertwines in DK Rises).
If they're going to use Megatron, then I'd like to see a reboot. If they're going to maintain continuity with the previous 3 films, then I'd rather not see Megatron appear; because then it just makes deaths in the story completely frivolous. And not even writers of the G1 cartoon wanted to do that... sure, they brought Optimus Prime back, but that was because Hasbro received a lot of flak from the public after having traumatised kids by killing Prime off in TFTM... and even then they held it out until the very end of Season 3 to bring Prime back properly. Once a character's death loses meaning, it's hard to emotionally connect to that character at all. TF1, Megatron had his Spark destroyed -- then he came back. In DOTM he had his head and spine ripped out and crushed... if the survives that then what's the impetus to care about this villain? They blow him up? Meh, he'll probably survive that too. He becomes more like some kind of Freddy Kruger monster rather than a character to care about, even as a villain (like Bane, Darth Vader or even Rampage in Beast Wars). At best he becomes like a comic relief character like Waspinator or Kenny from South Park.
"Oh my God, they killed Megatron!"
"You sons-of-unwed-parents!"