I would prefer to mimick importlib._bootstrap_external which uses:

def _pack_uint32(x):
    """Convert a 32-bit integer to little-endian."""
    return (int(x) & 0xFFFFFFFF).to_bytes(4, 'little')

Using 64-bit timestamp (PR 19651), treat timestamp as unsigned (PR 9892 and PR 19708) have drawback:

* 64-bit timestamp make .pyc files larger
* unsigned timestamp no longer support timestamp before 1969 which can cause practical issues

"& 0xFFFFFFFF" looks dead simple, uses a fixed size of 4 bytes and doesn't have any limitation of year 2038.

The timestamp doesn't have to be exact. In practice, it sounds very unlikely that two timestamps are equal when compared using (ts1 & 0xFFFFFFFF) == (ts2 & 0xFFFFFFFF). I expect file modification times to be close by a few days, not separated by 2**32 seconds (136 years).

Use hash based .pyc to avoid any issuse with file modification time: it should make Python more deterministic (more "reproducible").
https://docs.python.org/dev/reference/import.html#pyc-invalidation