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Figure 3: Principle underlying the imaging of HIF-1-active tumor microenvironments, using pretargeted POS and 18F-FBB. The PTD enables the delivery of POS to all tissues. In normoxic tissues, POS degrades in a manner similar to HIF-1α. In contrast, in hypoxic tissues, POS escapes degradation and is retained inside the cells. After allowing sufficient time for POS to degrade in normal tissues, 18F-FBB is administered. 18F-FBB enters cells by passive diffusion and binds to the SAV moiety of the POS retained in hypoxic cells; this does not occur in normoxic tissues. Therefore, pretargeting POS followed by 18F-FBB administration enables specific imaging of HIF-1-active hypoxic microenvironments.