The present invention provides diagnostic imaging contrast agents which exhibit improved blood retention. The novel compounds comprise: a) an image-enhancing (or signal-generating) moiety (IEM); b) a plasma protein binding moiety (PPBM); and c) a blood half-life extending moiety (BHEM). This invention also relates to pharmaceutical compositions comprising these compounds and to methods of using the compounds and compositions for blood half-life extension and contrast enhancement of diagnostic imaging. These contrast agents exhibit reduced rates of both renal and hepatocellular uptake and no apparent uptake by the RE system. The agents may be targeted to the blood pool or any other biological component. Since the agent is lost less rapidly from the bloodstream, lower doses can be used at a higher margin of safety. The approach is general to both large and small molecules.