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Am J Nucl Med Mol Imaging 2013;3(5):425-436
Original Article
Synthesis and in vivo evaluation of an 18F-labeled glycoconjugate of PD156707 for
imaging ETA receptor expression in thyroid carcinoma by positron emission
tomography
Simone Maschauer, Kristin Michel, Philipp Tripal, Katrin Büther, Torsten Kuwert, Otmar Schober, Klaus Kopka, Burkhard Riemann,
Olaf Prante
Department of Nuclear Medicine, Laboratory of Molecular Imaging and Radiochemistry, Friedrich-Alexander University, 91054
Erlangen, Germany; Department of Nuclear Medicine, University Hospital Münster, 48149 Münster, Germany; New address:
Radiopharmaceutical Chemistry, German Cancer Research Center (dkfz), 69120 Heidelberg, Germany
Received August 22, 2013; Accepted September 4, 2013; Epub September 19, 2013; Published September 30, 2013
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 [18F]1 was achieved by concomitant 18F-labeling and glycosylation,
providing [18F]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 [18F]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 18F-glycoconjugate was more stable in blood during PET recordings than was the previously
described 18F-fluoroethoxy analog. Small-animal PET imaging showed displacable binding of [18F]1 at ETAR in K1 tumors. The
simple and efficient 18F-radiosynthesis together with the excellent stability make the 18F-labeled glycoconjugate [18F]1 a promising
molecular tool for preclinical PET imaging studies of ETAR expression in thyroid carcinoma and other conditions with marked
angiogenesis. (ajnmmi1308004).
Keywords: Endothelin receptor, angiogenesis, positron emission tomography (PET), 18F, glycosylation, thyroid carcinoma
Address correspondence to: Dr. Olaf Prante, Department of Nuclear Medicine, Laboratory of Molecular Imaging and
Radiochemistry, Friedrich-Alexander University, Schwabachanlage 6, D-91054 Erlangen, Germany. Tel: +49 9131-8544440; Fax: +49
9131-8534440; E-mail: olaf.prante@uk-erlangen.de
Original Article
Synthesis and in vivo evaluation of an 18F-labeled glycoconjugate of PD156707 for
imaging ETA receptor expression in thyroid carcinoma by positron emission
tomography
Simone Maschauer, Kristin Michel, Philipp Tripal, Katrin Büther, Torsten Kuwert, Otmar Schober, Klaus Kopka, Burkhard Riemann,
Olaf Prante
Department of Nuclear Medicine, Laboratory of Molecular Imaging and Radiochemistry, Friedrich-Alexander University, 91054
Erlangen, Germany; Department of Nuclear Medicine, University Hospital Münster, 48149 Münster, Germany; New address:
Radiopharmaceutical Chemistry, German Cancer Research Center (dkfz), 69120 Heidelberg, Germany
Received August 22, 2013; Accepted September 4, 2013; Epub September 19, 2013; Published September 30, 2013
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 [18F]1 was achieved by concomitant 18F-labeling and glycosylation,
providing [18F]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 [18F]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 18F-glycoconjugate was more stable in blood during PET recordings than was the previously
described 18F-fluoroethoxy analog. Small-animal PET imaging showed displacable binding of [18F]1 at ETAR in K1 tumors. The
simple and efficient 18F-radiosynthesis together with the excellent stability make the 18F-labeled glycoconjugate [18F]1 a promising
molecular tool for preclinical PET imaging studies of ETAR expression in thyroid carcinoma and other conditions with marked
angiogenesis. (ajnmmi1308004).
Keywords: Endothelin receptor, angiogenesis, positron emission tomography (PET), 18F, glycosylation, thyroid carcinoma
Address correspondence to: Dr. Olaf Prante, Department of Nuclear Medicine, Laboratory of Molecular Imaging and
Radiochemistry, Friedrich-Alexander University, Schwabachanlage 6, D-91054 Erlangen, Germany. Tel: +49 9131-8544440; Fax: +49
9131-8534440; E-mail: olaf.prante@uk-erlangen.de
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