This smells a bit like a routing issue of some sort, though I'd start with the usual suspects:
1. Can the LTM see the SMTP servers? What happens if you log into the LTM and telnet to port 25 on the SMTP servers?
2. Do the SMTP servers show as 'up' in their pool? If you're using a monitor, is it correctly (or incorrectly) marking them up or down as appropriate?
3. What does a tcpdump show when a connection is made on the VIP/external side? and the internal side?
4. Anything oddball in the logs on your SMTP server or in /var/log/ltm on the LTM?
One or more of these should get you on the right track.
The 'smtp' profile comes into use if you're running ASM or ASM - it's used to hook the security features of those 2 products, and is otherwise not needed. It works the same way as an HTTP class profile does, except for SMTP.