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

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.