For adults, the Gaslamp district is probably the place you want to be. Good nightlife, lots of restaurants, bars, galleries, shopping. I'd probably rent a car no matter where I stayed if I wanted to check out a lot of different areas like beaches, SD Zoo, Sea World, Old Town, Coronado Island, etc. Horton Plaza has probably the coolest architecture for a mall experience that both adults and kids can enjoy. La Jolla is beautiful, but not a lot to do outside of the beach and high-end shopping. But staying near the nightlife (if that's your thing) is probably the best idea no matter where you go for the day so I'd stay near the Gas Lamp. Bunch of high rise hotels with great views in that area. Pricey, but that's San Diego.