Sadly, I haven't had too many long-runner games, so most of the best antagonists have been one-off villains we defeat and move on from. But I can talk about how I try to craft compelling antagonists, both short-term and long-term.
One path is what I'll call the "smug bastard" villain. The kind who is just so...so...punchable, y'know? Someone you get a perverse joy out of hating, and are filled with the most delicious schadenfreude when they get (proverbially or literally) kicked in the teeth. Developing this kind of antagonist doesn't take a ton of effort, but it does require you to at least preserve their veneer of calm, collected villainy for a while so that the players messing up the villain's plans feels sufficiently weighty. A villain that exploits social dynamics to protect themselves, taunts the PCs with how untouchable they are, gets irritatingly successful in ways the PCs can't just easily take away--that's how you make this person both memorable and oh-so-hateworthy.
Another memorable path is the "force of nature" villain. Someone, or perhaps something, that is so enormously, overwhelmingly powerful that they can't do anything about it--yet. This offers a way for the players to really see how their characters grow over time. A villain that was practically a walking natural disaster transitions from "JUST RUN" to "okay, manage the danger" to "we can hamper this" to "we can stop this." It helps to create defenses that the PCs can use to reliably protect themselves under certain circumstances, so they aren't constantly running scared, but instead focused on figuring out what they can DO about this horrendously powerful threat. It doesn't need to be personal in any way--it really can just be a natural disaster on legs!--but it can feel personal if the devastation it wreaks affects the things and people that the PCs care about.
A third path is the "True Believer." This can even be someone who starts out, perhaps even sincerely, helping the PCs, only for their real beliefs (not necessarily "allegiance" per se) to be revealed later. A good example there could be a well-heeled and benevolent professor, who secretly leads a Cthulhu cult after being indoctrinated on an archaeological dig or the like. Other True Believers can be people with royalist/imperialist sympathies who are otherwise friendly and helpful, business moguls who see themselves as philanthropists but who are actually the cause of great misery through their reckless business actions, or mad scientists who supply the party with useful things to start off with but go on to commit atrocities in the name of SCIENCE!!!
One final path is the "Noble Demon" villain, especially if they're of the "affable evil" persuasion where they're genuinely likeable, just...evil. In a sense, this is sort of the antithesis of the True Believer. It's someone who really could be your ally, if only they'd stop aiming to rule the world (or whatever)--their behavior is generally upstanding, they treat their employees well etc., etc., they're just trying to take over the world or unleash a plague and then sell the cure for huge bucks or whatever else. This villain can work really well if you're able to pull off the "James Bond Villain Dinner" type stuff, where the villain shows they're a gracious host, a good conversationalist, a surprisingly soft or relatable sort in pure socialization, where the moral quandaries of the rest of the world momentarily cease to be at the forefront.
In almost every case, building up a good antagonist comes down in part to how you portray them and what interactions they have with the party. Affable villains need chances to show that they "have standards", that they care about doing things the right way for the right reason (they just disagree about what reasons are "right"). Force of Nature villains need chances to show their awe-inspiring, overwhelming power in ways that don't just obliterate the PCs. True Believers are going to betray the party at some point; for that betrayal to land, the party has to value their connection before the treachery is revealed. Smug Bastards need to be impressively composed, so that the party wants to see that composure break. Etc.
There is no formula for doing this right. It's a matter of both your charisma as a performer, and giving the villains "rational" minds (for a given definition of "rational", since I included Cthulhu cultists in here!), goals that befit their skill/power level and interests, and concrete actions that further their villainy unless thwarted.