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

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 model, which showed the highest tumor uptake
(3.63 ± 0.32%ID/g at 0.5 h) and excellent tumor/nontumor contrast
(7.65 ± 1.14 at 1 h). The tracer remained stable in blood for
over 2 h without causing toxicity. These findings highlight CTSD as
a key cancer biomarker and demonstrate the potential of this radiotracer
for improving early cancer detection and monitoring therapy response
in patients.