Synthesis and in Vivo Evaluation of [123I]Melanin-Targeted Agents

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• 作者：Maxine P. Roberts ; Vu Nguyen ; Mark E. Ashford ; Paula Berghofer ; Naomi A. Wyatt ; Anwen M. Krause-Heuer ; Tien Q. Pham ; Stephen R. Taylor ; Leena Hogan ; Cathy D. Jiang ; Benjamin H. Fraser ; Nigel A. Lengkeek ; Lidia Matesic ; Marie-Claude Gregoire ; Delphine Denoyer ; Rodney J. Hicks ; Andrew Katsifis ; Ivan Greguric
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：August 13, 2015
• 年：2015
• 卷：58
• 期：15
• 页码：6214-6224
• 全文大小：466K
• ISSN：1520-4804

文摘

This study reports the synthesis, [¹²³I]radiolabeling, and biological profile of a new series of iodinated compounds for potential translation to the corresponding [¹³¹I]radiolabeled compounds for radionuclide therapy of melanoma. Radiolabeling was achieved via standard electrophilic iododestannylation in 60鈥?0% radiochemical yield. Preliminary SPECT imaging demonstrated high and distinct tumor uptake of all compounds, as well as high tumor-to-background ratios compared to the literature compound [¹²³I]4 (ICF01012). The most favorable compounds ([¹²³I]20, [¹²³I]23, [¹²³I]41, and [¹²³I]53) were selected for further biological investigation. Biodistribution studies indicated that all four compounds bound to melanin containing tissue with low in vivo deiodination; [¹²³I]20 and [¹²³I]53 in particular displayed high and prolonged tumor uptake (13%聽ID/g at 48 h). [¹²³I]53 had the most favorable overall profile of the cumulative uptake over time of radiosensitive organs. Metabolite analysis of the four radiotracers found [¹²³I]41 and [¹²³I]53 to be the most favorable, displaying high and prolonged amounts of intact tracer in melanin containing tissues, suggesting melanin specific binding. Results herein suggest that compound [¹²³I]53 displays favorable in vivo pharmacokinetics and stability and hence is an ideal candidate to proceed with further preclinical [¹³¹I] therapeutic evaluation.