I tripped over this today – if you're using a custom build of IronPython (such as one built in debug mode), then any extensions have to be rebuilt against that build of IronPython.
This occurs because the references in the extensions are against the official builds, which are signed (strong-named), but a custom IronPython build is not signed (or signed with a different key).
Another option would be to build the extensions with a non-strong-named reference to IronPython, but I don't if this is possible or how to do it. If anyone else does, please let me know!