Fluorine-18 and iodine-124 labeled cyclin-dependent kinase 4 and 6 inhibitors as radiotracers for tumor imaging by positron emission tomography (PET)


Fluorine-18 and iodine-124 labeled cyclin-dependent kinase 4 and 6 inhibitors as radiotracers for tumor imaging by positron emission tomography (PET)

Graf, F.; Bergmann, R.; Koehler, L.; Mosch, B.; Steinbach, J.; Wuest, F.; Pietzsch, J.

Background
Cyclin-dependent kinases 4 and 6 (Cdk4/6) function as critical activators of cell cycle progression in human tumors. Pyrido[2,3 d]pyrimidine derivatives CKIA and CKIE are selective Cdk4/6 inhibitors with high potency for the inhibition of G1 phase progression and tumor cell proliferation. The aim of this study was the evaluation of radiolabeled compounds [124I]CKIA and [18F]CKIE as radiotracers for PET imaging of Cdk4/6 in tumors in vivo.

Materials and methods
Cellular uptake of radiotracers [124I]CKIA and [18F]CKIE was studied in human colorectal (HT-29) and squamous cell (FaDu) carcinoma cells. Small animal PET studies of both radiotracers were performed in FaDu xenograft-bearing nude mice.

Results
Radiotracer uptake studies showed fast and high uptake (up to 800%ID/mg protein) of [124I]CKIA in both cell lines after 1 h at 37°C. Cellular uptake of [18F]CKIE was lower (HT 29, 46.3±11.2%ID/mg protein; FaDu, 46.2±13.8%ID/mg protein). Radiotracer uptake was significantly lower at 4°C for [124I]CKIA (150%ID/mg protein) and [18F]CKIE (15%ID/mg protein) after 1 h in both cell lines. Cellular uptake of [18F]CKIE was reduced to 18.0±4.9%ID/mg protein in the presence of 10 µM of nonradioactive CKIE at 37°C. Dynamic small animal PET studies showed rapid clearance of [124I]CKIA and [18F]CKIE from the blood and fast hepatobiliary excretion. The half-life of radiotracer elimination from the blood was calculated to be 7.2 min for [124I]CKIA and 7.9 min for [18F]CKIE, respectively. Radiotracers were rapidly metabolized in blood in vivo, yielding >90% (1 min p.i.), 20% (30 min), and <5% (1 h) of the original compounds. Small animal PET studies with [124I]CKIA only showed marginal uptake of the radiotracer in the FaDu tumor. In the case of [18F]CKIE a higher uptake was detected in the peripheral proliferative region of the tumor after 1 h p.i. However, the constant tumor-to-muscle ratio of 1.5 suggests a non-Cdk4/6-mediated uptake of [18F]CKIE in human tumor xenografts in mice.

Conclusions
Synthesis of pyrido[2,3-d]pyrimidine-based radiotracers [124I]CKIA and [18F]CKIE allowed for the first time the quantification of cellular uptake in vitro and imaging of tissue-specific distribution of Cdk4/6 inhibitors in vivo. However, the short biological half-life in the blood and low tumor uptake of [124I]CKIA and [18F]CKIE limit the use of both radiotracers for the characterization of Cdk4/6 expression in tumors by means of PET. Further development of suitable radiolabeled Cdk4/6 inhibitors for functional characterization of Cdk4/6 in tumors continues to be of great interest in current translational cancer research.

  • Poster
    21st Meeting of the European Association for Cancer Research (EACR-21), 26.-29.06.2010, Oslo, Norway
  • Open Access Logo Abstract in refereed journal
    European Journal of Cancer 8(2010)5, 61

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Publ.-Id: 14257