Design and Preclinical Evaluation of First 68Ga-Labeled Cathepsin D‑Targeted Radiotracers

Abstract Cathepsin D (CTSD), a lysosomal aspartic protease linked to cancer progression and poor patient outcomes, is underexplored as a diagnostic biomarker. This study developed the first CTSD-targeted radiotracers, identifying [68Ga]­Ga-NOTA-FZCD-3 as optimal due to its strong binding to CTSD (dissociation constant = 0.65 μM), rapid clearance from the body (elimination half-life = 16.61 min), and high tumor-specific uptake in mouse models. Imaging analysis revealed that tumors with higher CTSD levels absorbed more of the tracer, particularly in the MDA-MB-175VII