The study of the Seleucids in recent times has, in general, tried to move away from concentrating on its decline/collapse, probably because for a while that's all anybody ever wanted to talk about when the subject of the Seleucids came up, and it was all they were ever known for. However... the fact that they did lose territory earlier and more obviously than, say, the Achaemenids did is unavoidable, and your question is one that inevitably needs answering.

For my money, it's because the situation the Seleucids faced was not the same as that faced by the Achaemenids, despite occupying much of the same territory and inheriting much of its bits and bobs. The world by the death of Seleucus I in 280 BCE was fundamentally different compared to the world as it had existed across the lifetime of the Achaemenids. Regardless of the internal situation of Seleucid territories, and their inheritance of the robust Achaemenid bureaucratic machine (along with imperial infrastructure), external factors blended with the particular situation that Seleucus I and Antiochus I inherited guaranteed that the Seleucid experience was going to be a wild ride. Let's get into particulars.

The End of Hegemony

The Achaemenids, after the reign of Cyrus I, were effectively hegemons of their stated boundaries, only struggling to project power unilaterally at the very extreme frontiers of the Empire (i.e Greece, the Indus, Egypt, the Central Asian steppe). For around two centuries no real force existed to attempt to uproot them. The only real military threat the Empire experienced, until Alexander's time, came from rival dynastic claimants. I think an underexplored reason for this is that, by the mid-late 6th century BC, the Achaemenids had already occupied all of the nascent imperial powers of that period, and most of the urbanised regions in or adjacent to the Near East. There were no major, rival centres of geopolitical gravity left by the time Cambyses I had conquered Egypt. Alexander's invasion was not only the first time (that we're aware of) an external power actually attempted to conquer the Achaemenids, it was also not joined by any similar attempts from any of the Empire's other frontiers even after it was clear the war was going to resolve in Alexander's favour.

Alexander's conquest itself called that hegemony into question, establishing that a sufficiently motivated and well-led party was able to bulldoze its way into control over the entire Achaemenid apparatus. However, I think the real 'damage' to the notion of imperial hegemony came from the structural impact of Alexander's conquest and the fallout over his death. What I mean by the former is that Alexander did not simply replace the Achaemenid dynasty with his own whilst keeping everything else the same, despite his intentions.

He and his father before him had already built Macedon into its own centre of imperial power in the Eastern Mediterranean, one capable of mounting a sustained military campaign for almost a decade and maintaining a military hegemony on most of mainland Greece through that period. Anyone who controlled Macedon possessed real power, even if they didn't maintain control over Alexander's conquests in the Near East, and it had now been established that Macedon was an imperial centre with interests directed into Anatolia and beyond. But Alexander's campaign affected more changes than just in Macedon. The 'cities' he founded on campaign were almost always on the site of an existing fort or city, and the evidence suggests they were more like garrisons. Nonetheless, by having the prestige+authority of the King attached to them, and by strengthening the military influence of these sites, he absolutely affected the balance of power in those regions from their Achaemenid era status quo, and made them crucial possessions for whomever came after him. This not only affected the regions these foundations were made in but also the balance between regions of the Empire. This also happened when he was seen to 'elevate' Egypt's position within the Empire, not only by securing it without bloodshed but also by allowing Egypt to create ideological ties to him, and allowing himself to be portrayed as at least semi-divine via the cult of the god Ammon.

His campaign also seeded changes outside of the Empire's borders- the Achaemenid status quo in the Indus region and beyond is extremely poorly documented, but it's not far-fetched to imagine a situation analagous to Greece by the late 5th/early 4th century BC where a balance of power was maintained, partially through strategic deployment of Achaemenid treasure and support to various cocktails of client powers. Alexander's campaigning in India definitely reset the Achaemenid era status quo in that region, whatever it was, disrupting the existing network of states that existed in his areas of campaign and subverting the authority/prestige of Indian states across a wider area. This, and possibly the awareness that Northern India was now Of Interest to external conquerors, set the stage for the emergence of the subcontinent spanning Mauryan Empire. Some later Indian historians even described a meeting between Alexander and Chandragupta Maurya, the Empire's founder. Alexander's sidestepping of Armenia and the Caucasus, where imperial authority had not been asserted even by the time of his death, also afforded that region the opportunity to accrue autonomy and controlling interests in the region.

His death, for me, is also a crucial factor in bursting the bubble of uncontested hegemony. We can speculate as to how stable his Empire would or would not have been across an imagined longer lifespan, or if his son had been an adult by the time he had died, but we know just how fractious and internecine matters became as a result of his historical death, whilst his direct heir was still a child and when he had not been unquestioned ruler of the Achaemenid domains for particularly long. Not only was there a constant parade of would-be-hegemons and brief potentates, many of whom constantly backstabbed one another, there was also, for the first time, multiple claimants to the rank of king once a few years passed after Alexander's death. One of the key principles of the Achaemenid hegemony, and indeed Alexander's, is that there was only ONE king of everything in the Empire. The existence of alternate figures with that title for extended periods was itself hugely damaging to the notion of a single Empire to which all of these places ultimately 'belonged'. In a situation where one is constantly seeing various minor figures rise and fall, and where 'authority' is almost entirely based on what one can grab and hold onto, it is not exactly an environment promoting the idea that a single authority figure is your unquestioned sovereign. The wars of the Successors were a period of near-total chaos.

Then you have the changes to the world stage not related to Alexander. The one I think is most relevant to Seleucid territorial integrity, and the notion of its hegemony, is the beginning of massive changes to the Eurasian steppe resulting in a chain reaction of migrations and conquests by steppe peoples, which is part of why the Seleucid frontier in Central Asia was more frequently pushed at. The combination of this and clever opportunism transformed the Parthian satrap's break for independence, which might well have resulted in a situation similar to the Greco-Bactrian state, into a foot in the door for the Dahae confederacy to establish itself in Parthia, and in doing so laid the seeds for the Seleucid state's ultimate nemesis in the Middle East to emerge later on- the Arsacid Empire. Variations on these pressures from the steppe would reassert themselves on many later west Asian empires and states, from the collapse of the Greco-Bactrian state to the Sasanian wars against the Hephalites and the Goturks.

Conclusion

What this boils down to is the Seleucids could, to my mind, never have realistically maintained the same kind of unquestioned international authority and territorial integrity that the Achaemenids did. That notion of invincibility had been well and truly shattered, and the Seleucids would forever have to live with the existence of peers that could and would push back, from the war with the Mauryans that gave them territorial concessions in Arachosia to its constant wars with Egypt and Macedon. There were no equivalents to any of these peer level powers for the Achaemenids and it's not without relevance, I think, that the minute it acquired a peer that formed aggressive plans over its territorial hegemony in the form of Macedon the Achaemenid dynasty was rolled up like a carpet, albeit not without heavy resistance. Even if the Seleucids had somehow conquered Macedon early, and potentially Egypt later, I think a version of this nibbling by various breakaway satrapies and external powers was always on the cards.

One final note I'd leave is about Syria- after Seleucus died in his campaign to secure Macedon, the 'homeland' and heartland of the Seleucid dynasty was conceived of as being Syria. After all, plenty of other Greeks never conceived their personal homeland as being mainland Greece, so this was not necessarily an ideological stretch, particularly as by Seleucus' death there had already been significant Greek settlement in Syria at the direction of the Antigonids and Seleucus himself. Antiokheia on the Orontes, modern Antioch, was founded by Seleucus and functioned as a de facto imperial capital for the Seleucids even before the loss of Mesopotamia. From Antiochus I's reign onwards the best way to think of Syria is like the Seleucid analogy to Persia for the Achaemenids- it served both as their 'homeland' within the Empire but also as the synonym for the Empire as a whole. This is in case you were curious as to why it was Syria in particular that was retained by the Seleucid rump state.