Abstract
Disturbances of the endothelin axis have been described in tumor angiogenesis and in highly vascularized tumors, such as thyroid carcinoma. Consequently, the endothelin (ET) receptor offers a molecular target for the visualization of the endothelin system in vivo by positron emission tomography (PET). We therefore endeavoured to develop a subtype-selective ETA receptor (ETAR) radioligand by introduction of a glycosyl moiety as a hydrophilic building block into the lead compound PD156707. Employing click chemistry we synthesized the triazolyl conjugated fluoroglucosyl derivative 1 that had high selectivity for ETAR (4.5 nM) over ETBR (1.2 μM). The radiosynthesis of the glycoconjugate [(18)F]1 was achieved by concomitant (18)F-labeling and glycosylation, providing [(18)F]1 in high radiochemical yields (20-25%, not corrected for decay, 70 min) and a specific activity of 41-138 GBq/μmol. Binding properties of [(18)F]1 were evaluated in vitro, and its biodistribution was measured in K1 thyroid carcinoma xenograft nude mice ex vivo and by molecular imaging. Although the very substantial excretion via hepatobiliary clearance was not decisively influenced by glycosylation, the (18)F-glycoconjugate was more stable in blood during PET recordings than was the previously described (18)F-fluoroethoxy analog. Small-animal PET imaging showed displacable binding of [(18)F]1 at ETAR in K1 tumors. The simple and efficient (18)F-radiosynthesis together with the excellent stability make the (18)F-labeled glycoconjugate [(18)F]1 a promising molecular tool for preclinical PET imaging studies of ETAR expression in thyroid carcinoma and other conditions with marked angiogenesis.