Radiosynthesis and radiopharmacological evaluation of cyclin-dependent kinase 4 (Cdk4) inhibitors

Tumor cells are characterized by their loss of growth control resulting from alterations in regulating pathways of the cell cycle, such as a deregulated cyclin-dependent kinase (Cdk) activity and/or Cdk expression. Appropriately radiolabeled Cdk4 inhibitors are discussed as promising molecular probes for imaging cell proliferation processes and tumor visualization by PET. This work describes the design, synthesis and radiopharmacological evaluation of two ¹²⁴I-labeled Cdk4 inhibitors as potential radiotracers for imaging of Cdk4 in vivo. Treatment of a solution containing labeling precursors with [¹²⁴I]NaI gave radiolabeled Cdk4 inhibitors [¹²⁴I]CKIA and [¹²⁴I]CKIB in radiochemical yields of up to 35%. ¹²⁴I-labeled radiotracers [¹²⁴I]CKIA and [¹²⁴I]CKIB were used in cell uptake studies as well as biodistribution studies in Wistar rats and small-animal PET in tumor-bearing mice. In vitro radiotracer uptake studies in adherent tumor cells using [¹²⁴I]CKIA showed substantial uptake in HT-29 and FaDu cells (750–850 %ID/mg protein [¹²⁴I]CKIA and 900–1000 %ID/mg protein [¹²⁴I]CKIB) after 1 h at 37 °C. Biodistribution of [¹²⁴I]CKIA and [¹²⁴I]CKIB showed rapid blood clearance of radioactivity and an accumulation as well as metabolization in the liver. Both radiotracers were administered intravenously to mouse FaDu xenograft tumor model and imaging studies were performed on a small-animal PET scanner. Both imaging techniques showed only little uptake of both radiotracers in the FaDu tumor xenografts.