Loadbalance SMTP relay on F5 and exchange 2010

Do you have BIG-IP doing SNAT (source address translation)? This would be set as a property on the virtual server.

My first guess is that you have SNAT enabled. If you disable SNAT, the remote Hub server should see the connection as originating with the IP address of the Hub server(s) and should allow a connection to the custom receive connector.

You may have to adjust routing in your environment to get this to work without SNAT; the important configuration detail is that each destination server needs to have a route back to the source server though the BIG-IP.

Please let us know if SNAT is enabled and if disabling it (and adjusting routing, if needed) solves the problem. If that doesn't work, please open a support case with F5 so we can take a look at more-detailed aspects of your configuration.