Advances in radiolabelled CDK4/6 inhibitors for in vivo imaging of CDK4/6 activity in tumours.

Dysregulated cyclin D-CDK4/6-Rb signalling drives uncontrolled proliferation in patients with breast cancer and other malignancies. Although CDK4/6 inhibitors improve patient outcomes, their efficacy is limited by resistance and toxicity, necessitating noninvasive monitoring tools. This review comprehensively analyses the development of radiolabelled CDK4/6 inhibitors for in vivo PET/SPECT imaging. Capitalizing on the solvent-exposed piperazine moiety, F-, Ga-, and Tc-labelled radiotracers achieve targeted visualization of CDK4/6 activity. However, more than 80% of radiotracers suffer from excessive hepatobiliary excretion and persistent blood retention. Strategic linker engineering, such as short alkyl chains and PEG spacers, mitigates steric hindrance from bulky chelators. Advances in one-step radiosynthesis and computational design address synthetic and pharmacokinetic challenges. Future efforts should focus on simplifying radiosynthesis protocols, optimizing pharmacokinetics to reduce nontargeted uptake, and integrating computational modelling (docking/dynamics) with experimental validation to refine linker design while advancing towards clinical trials. These innovations promise to transform precision oncology by enabling real-time therapy response assessment and early resistance detection.