title: Development and evaluation of endothelin-A receptor (radio)ligands for positron emission tomography.
abstract: The expression and function of endothelin (ET) receptors are abnormal in cardiovascular diseases, tumor progression, and tumor metastasis. A previously reported promising radioligand for positron emission tomography (PET) based on the non-peptide ET(A) receptor antagonist PD 156707 showed specific binding to target receptors in the myocardium but high accumulation in bile and intestine, probably because of its high lipophilicity. In this study we describe the synthesis of a series of fluorinated derivatives with hydrophilic building blocks. All compounds were evaluated as high affinity ET(A) receptor ligands (16, 17, 23-26, K(i) = 1.4-7.9 nM) with high subtype selectivity over the ET(B) receptor. [(18)F]3-Benzo[1,3]dioxol-5-yl-4-{3-[1-(2-{2-[2-(2-fluoroethoxy)ethoxy]ethoxy}ethyl)-1H-[1,2,3]triazol-4-ylmethoxy]-4,5-dimethoxybenzyl}-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one ([(18)F]17) was synthesized as one of the radioligands of this series that possesses a higher hydrophilicity and an excellent stability in human serum. Improved clearance properties and specific uptake in target organs have been confirmed by biodistribution studies and small animal PET imaging.
authors.affiliation: Department of Nuclear Medicine, University Hospital Münster, Albert-Schweitzer-Strasse 33, D-48149 Münster, Germany. kristin.michel@uni-muenster.de
authors.forename: Kristin
authors.initials: K
authors.lastname: Michel
authors.forename: Katrin
authors.initials: K
authors.lastname: Büther
authors.forename: Marilyn P
authors.initials: MP
authors.lastname: Law
authors.forename: Stefan
authors.initials: S
authors.lastname: Wagner
authors.forename: Otmar
authors.initials: O
authors.lastname: Schober
authors.forename: Sven
authors.initials: S
authors.lastname: Hermann
authors.forename: Michael
authors.initials: M
authors.lastname: Schäfers
authors.forename: Burkhard
authors.initials: B
authors.lastname: Riemann
authors.forename: Carsten
authors.initials: C
authors.lastname: Höltke
authors.forename: Klaus
authors.initials: K
authors.lastname: Kopka
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D057930:Click Chemistry / Q000379:methods; D065130:Endothelin A Receptor Antagonists; D005462:Fluorine Radioisotopes; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D008807:Mice, Inbred BALB C; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry; D051381:Rats; D044022:Receptor, Endothelin A / Q000378:metabolism*; D014018:Tissue Distribution; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: D065130:Endothelin A Receptor Antagonists; D005462:Fluorine Radioisotopes; D005663:Furans; D008024:Ligands; D019275:Radiopharmaceuticals; D044022:Receptor, Endothelin A; D014230:Triazoles