Most gas-filled ultrasound contrast agents are produced range of severalmicrons in diameter, which limits them to flow within intravascular space. Onemechanism proposed to produce extravascular imaging agents is acoustic dropletvaporization. Liquid perfluorocarbon droplets can be manufactured in thesub-micron range and can then passively diffuse through leaky tumor vasculature.It is hypothesized that once extravasated, these droplets could be converted tomicrobubbles in the micron range through additional energy input in the form ofultrasound, resulting in enhanced imaging contrast. Recent studies show currentformulations of phase-change contrast agents in the sub-micron range mayrequire substantial acoustic energy to vaporize, which increases the chance ofbioeffects. Thus, phase-change contrast agents with reduced acoustic activationenergies would have significant advantages. In this study, the generation andactivation of novel phase-change contrast agents formulated with perfluorobutaneis demonstrated. Perfluorobutane normally a gas at room temperature can beincorporated into metastable liquid sub-micron droplets with lipid encapsulationmethods. The resulting droplets are shown to be acoustically vaporizable withsubstantially less energy than other compounds proposed for phase-changecontrast agents such as perfluoropentane and perfluorohexane.