Enhanced Tumor Retention of a Radiohalogen Label for Site-Specific Modification of Antibodies

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• 作者：C. Andrew Boswell ; Jan Marik ; Michael J. Elowson ; Noe A. Reyes ; Sheila Ulufatu ; Daniela Bumbaca ; Victor Yip ; Eduardo E. Mundo ; Nicholas Majidy ; Marjie Van Hoy ; Saritha N. Goriparthi ; Anthony Trias ; Herman S. Gill ; Simon P. Williams ; Jagath R. Junutula ; Paul J. Fielder ; Leslie A. Khawli
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：December 12, 2013
• 年：2013
• 卷：56
• 期：23
• 页码：9418-9426
• 全文大小：417K
• 年卷期：v.56,no.23(December 12, 2013)
• ISSN：1520-4804

文摘

A known limitation of iodine radionuclides for labeling and biological tracking of receptor targeted proteins is the tendency of iodotyrosine to rapidly diffuse from cells following endocytosis and lysosomal degradation. In contrast, radiometal鈥揷helate complexes such as indium-111鈥?,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (In-111-DOTA) accumulate within target cells due to the residualizing properties of the polar, charged metal-chelate-amino acid adduct. Iodine radionuclides boast a diversity of nuclear properties and chemical means for incorporation, prompting efforts to covalently link radioiodine with residualizing molecules. Herein, we describe the Ugi-assisted synthesis of [I-125]HIP-DOTA, a 4-hydroxy-3-iodophenyl (HIP) derivative of DOTA, and demonstration of its residualizing properties in a murine xenograft model. Overall, this study displays the power of multicomponent synthesis to yield a versatile radioactive probe for antibodies across multiple therapeutic areas with potential applications in both preclinical biodistribution studies and clinical radioimmunotherapies.