Radioiodinated sunitinib as a potential radiotracer for imaging angiogenesis鈥攔adiosynthesis and first radiopharmacological evaluation of 5-[¹²⁵I]Iodo-sunitinib

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• 作者：Manuela Kuchar^a ; Maria Cristina Oliveira^b ; Lurdes Gano^b ; Isabel Santos^b ; Torsten Kniess^a ; ^{t.kniess@hzdr.de}
• 关键词：Sunitinib® ; VEGFR ; RTKs ; Iodine-125 ; Radiolabeling
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：15 April, 2012
• 卷：22
• 期：8
• 页码：2850-2855
• 文件大小：412 K

摘要

Sunitinib庐 (SU11248) is a highly potent tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR). Radiolabeled inhibitors of RTKs might be useful tools for monitoring RTKs levels in tumour tissue giving valuable information for anti-angiogenic therapy. We report here the synthesis of a ¹²⁵I-labeled derivative of sunitinib庐 and its first radiopharmaceutical characterization.

The non-radioactive reference compound 5-iodo-sunitinib 4 was prepared by Knoevenagel condensation of 5-iodo-oxindole with the corresponding substituted 5-formyl-1H-pyrrole. In a competition binding assay against VEGFR-2 a binding constant (K_d) of 16 nM for 4 was found. The ability of 4 to inhibit tyrosine kinase activity was demonstrated on RTK expressing cells suggesting this radiotracer as a useful tool for monitoring VEGFR expression. 5-[¹²⁵I]lodo-sunitinib, [¹²⁵I]-4 was obtained via destannylation of the corresponding tributylstannyl precursor with [¹²⁵I]NaI in the presence of H₂O₂ in high radiochemical yield (>95%) and radiochemical purity (<98%) after HPLC purification. Determination of human plasma protein binding at time intervals of 0; 1; 2; 4 and 24 h suggested a low non-specific binding of 5-10%. Preliminary biodistribution studies of [¹²⁵I]-4 in healthy CD-1 mice showed a relatively high uptake in VEGFR-2 rich tissues like kidney and lung followed by rapid washout (9.6 and 9.7; 4.5 and 3.8%ID/g of kidney and lung at 1 and 4 h, respectively).