Development and Evaluation of Endothelin-A Receptor (Radio)Ligands for Positron Emission Tomography

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• 作者：Kristin Michel ; Katrin Bu虉ther ; Marilyn P. Law ; Stefan Wagner ; Otmar Schober ; Sven Hermann ; Michael Scha虉fers ; Burkhard Riemann ; Carsten Ho虉ltke ; Klaus Kopka
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：February 24, 2011
• 年：2011
• 卷：54
• 期：4
• 页码：939-948
• 全文大小：1031K
• 年卷期：v.54,no.4(February 24, 2011)
• ISSN：1520-4804

文摘

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鈭?b>26, K_i = 1.4鈭?.9 nM) with high subtype selectivity over the ET_B receptor. [¹⁸F]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 ([¹⁸F]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.