I would recommend your setting be in Seattle, simply because of the gigantic metric ton of information for the setting. When I'm coming up with a campaign, I try to think of recent events that have been outlined in the books and then get a spark. For example, the creation of the Orc Underground as a district of Seattle. There are people who wouldn't want that to happen on both sides of the metahuman fence. Humanis folks don't want it because it legitimizes the Orks and Trolls of the district. The Underground doesn't want it because they have to pay taxes, get SINs, etc. and now they're subject to Knight Errant patrols.
Let's say, for example, that there's an Ork who has pushing hard from the back for the passing of Proposition 23. Once the measure passed, the district became legitimate, so the ork's political ambitions grew. Now he wants to be the mayor of the district. To do so, he'll have to sway public opinion in favor of the district, take a hard stance against Knight Errant, and also push out Humanis. Once he's got his name on the ballot, then it's a matter of fixing the election in his favor by discrediting his enemies, literally stuffing the ballot boxes, and dissuading his opponent's supporters from voting. That's easily 10 or so games right there, and with a few one-offs thrown into the mix, you've got enough games to last quite a while.
The scenery for Seattle is very rich too - you've got the Underground, the Puyallup Barrens, and the Redmond Barrens. They all exist in stark contrast to the glittering green towers of Downtown, the mansions of Bellevue, and the embassies of Council Island. Within each district, there are power players vying for a bigger piece of the pie, which can include criminal activity, political ambition, corporate greed, or just street survival.
If you have an idea of what kind of power level you want to play at, it can help narrow things down a lot. If you're going for a gritty street game, where survival is the reason for running, then you probably want to stick to the various Barrens or Underground regions, with jaunts into the glitzy areas for contrast and to rub it in the players' faces. If you're going for the big time, you probably want to play things really tight with what is colloquially known as a "black trenchcoat" game. Spycraft, subterfuge, and assassination are the names of this game. Data thefts are common, but more common is planting misinformation and counterintelligence. The runners won't often know who hired them, but if they figure it out they might be able to make a payday - and an enemy.
I hope my rambling helps in some way, perhaps by inspiring you to try something out that you've never done before. If you need support (and we all do) that's what we're here for.
Welcome to the shadows.
