A Cyclic Peptide‐Based Radiotheranostic Agent for Urokinase‐Type Plasminogen Activator in Tumors

Abstract The plasminogen activator system is critically involved in tumor progression regulation. Aberrant activation of urokinase‐type plasminogen activator (uPA) induces proteolytic degradation of cellular membranes and the extracellular matrix, thereby promoting tumor invasion and metastasis. Consequently, uPA has emerged as a promising diagnostic and therapeutic target. Herein, we designed and evaluated three cyclic peptide‐based radioligands ([⁶⁴Cu]CAP‐1, [⁶⁴Cu]CAP‐2, and [⁶⁴Cu]CAP‐3) as potential PET tracers for uPA visualization in mouse tumor models, assessing their binding ability, specificity, and pharmacokinetic profiles. Among them, [⁶⁴Cu]CAP‐1, featuring a native disulfide bond, emerged as the optimal candidate. This radioligand demonstrated superior tumor uptake and reduced hepatic accumulation compared to the clinically advanced uPAR‐targeted tracer [⁶⁴Cu]DOTA‐AE105, currently in Phase 2 trials. A single administration of [⁶⁴Cu]CAP‐1 (2 mCi/mouse) significantly suppressed tumor growth and prolonged survival in mouse models. These findings position [⁶⁴Cu]CAP‐1 as a potent radiotheranostic agent for uPA‐overexpressing tumors, offering a novel strategy for precision targeting of the uPA/uPAR axis.