Molecular imaging of the endothelin-A-receptor expression as a benchmark of angiogenesis in murine thyroid cancer xenografts using small animal PET and optical imaging

Objectives A potential target for molecular imaging of angiogenesis in cancer is the endothelin-A-receptor (ETAR). A number of human cancer cell lines, e.g. thyroid cancer cell lines exhibit an upregulated density of ETAR, influencing tumor growth and aggressiveness. In this study, radio- and fluorescent-labeled ETAR antagonists were used for noninvasive evaluation of ET receptor expression in thyroid carcinoma xenografts using small animal PET and optical imaging techniques.

Methods Subcutaneous and orthotopic xenograft models of papillary thyroid carcinoma cells (K1) were established in CD-1 nude mice. RT-PCR analysis was used to evaluate ETAR expression of the tumors. A radiofluorinated analog of the known ETAR ligand PD 156707 was designed and applied in small animal PET experiments. A fluorescently labeled analog of PD 156707 was designed and used for optical imaging techniques such as FRI and FMT. By microautoradiography using 125I-ET-1 the binding of the fluorinated and the fluorescently labeled analogs to ET-A receptors on tumor sections was evaluated.

Results Using RT-PCR the expression of the ET-A receptor on human papillary thyroid carcinoma was confirmed. Small animal PET experiments showed accumulation of the ETAR-targeted radiotracer in the tumor. In optical imaging experiments, a high fluorescence signal was visible in the tumor region. Significant reduction in signal intensity was observed after predosing with lead compound PD 156707. In vitro autoradiography proved specific binding of the tracers to the ETAR in tumor sections.

Conclusions PET or optical imaging with radioisotope- or fluorescently labeled ET receptor ligands can be useful tools for the evaluation of the endothelin axis in tumoral lesions