Imaging CDK4/6 Broaden Options of Breast Cancer Diagnostics with Positron Emission Tomography

This study developed a novel PET radiotracer to screen breast cancer patients sensitive to CDK4/6 inhibitors, guiding personalized treatment. Two CDK4/6-targeting precursors were synthesized and evaluated <i>in vitro</i> and <i>in vivo</i>. Three breast cancer cell lines─MCF-7, MDA-MB-231, and MDA-MB-468─were selected based on decreasing sensitivity to palbociclib. Compared to [⁶⁸Ga]Ga-DOTA-Hexa-CDKi, [⁶⁸Ga]Ga-DOTA-Bua-CDKi clearly identified cell lines with high sensitivity to palbociclib. PET/CT imaging showed significantly higher uptake of [⁶⁸Ga]Ga-DOTA-Bua-CDKi (8.40 ± 0.85%ID/g) in MCF-7 tumors 60 min after tracer injection, with significant differences in tumor uptake among the three models (<i>P</i> < 0.05). Blocking assays demonstrated specific tumor uptake of [⁶⁸Ga]Ga-DOTA-Bua-CDKi. Biosafety tests validated its safety as a diagnostic agent. [⁶⁸Ga]Ga-DOTA-Bua-CDKi showed highly specific targeting of CDK4/6 and effective contrast imaging in tumor models. To our knowledge, [⁶⁸Ga]Ga-DOTA-Bua-CDKi is one of the first radiotracers to assess CDK inhibitor sensitivity, offering promise for evaluating patient responses to CDK4/6 inhibitors.