Noninvasive imaging tools that enable real-time visualization of biological events in living subjects are highly valuable in biomedical research. Bioluminescence imaging (BLI), with its high sensitivity and low background, provides an ideal platform for developing molecular sensors to monitor intracellular signaling in vivo . Here, we report the development of a kinase-modulated bioluminescent indicator (KiMBI) for rapid, noninvasive pharmacodynamic (PD) assessment of Akt-targeted therapeutics, substantially reducing compound use and animal requirements. This ATP-independent reporter, based on NanoLuc luciferase, produces light upon administration of the brain-penetrant substrate cephalofurimazine (CFz9). Using KiMBI, we performed a structure-PD relationship analysis of the brain-active Akt inhibitor ipatasertib by designing and characterizing two novel analogs. One analog, ML-B01, exhibited robust Akt inhibition in both brain and peripheral tissues. Remarkably, capivasertib, ipatasertib, and ML-B01 all demonstrated prolonged PD effects that outlasted their pharmacokinetic (PK) profiles. Furthermore, KiMBI imaging revealed that the PD effect of an Akt-targeted proteolysis-targeting chimera (PROTAC) degrader persisted for more than three days following a single dose. Together, these results establish bioluminescence imaging with the Akt KiMBI as a sensitive and efficient method for real-time, longitudinal visualization of Akt inhibitor and degrader activity in vivo. This platform offers a powerful approach for early-stage drug optimization and for elucidating the pharmacodynamics of kinase-targeted therapies in live animals.