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Abstract

One of the most clinically relevant molecular aberrations in breast cancer is overexpression of human epidermal growth factor receptor type 2 (HER2). We aimed to develop a radiolabeled tyrosine kinase inhibitor for HER2-targeted breast cancer imaging. In this study, a radioiodinated analog (^125/131I-IBA-CP) of the HER2-selective inhibitor CP724,714 was prepared and evaluated in HER2-positive or -negative subcutaneous human breast cancer xenografts. <b>Methods:</b> The CP724,714 analog IBA-CP was synthesized and assayed for its inhibitory activities against HER2 and 6 other tyrosine kinases. ^125/131I-IBA-CP was prepared using a copper-mediated radioiodination method with enhanced labeling yield and molar activity. In vitro biologic activity, including specific and nonspecific binding of ¹³¹I-IBA-CP to its HER2 kinase target, was assessed in different cell lines. In vivo small-animal ¹²⁵I-IBA-CP SPECT imaging and biodistribution studies were conducted on mice bearing HER2-positive, HER2-negative, or epidermal growth factor receptor (EGFR)-positive tumors. Nonradioactive IBA-CP and the EGFR inhibitor erlotinib were used as blocking agents to investigate the binding specificity and selectivity of ^125/131I-IBA-CP toward HER2 in vitro and in vivo. Additionally, ^125/131I-ICP was prepared by direct radioiodination of CP724,714 for comparison with ^125/131I-IBA-CP. <b>Results:</b> IBA-CP displayed superior in vitro inhibitory activity (half-maximal inhibitory concentration, 16 nM) and selectivity for HER2 over 6 other cancer-related tyrosine kinases. ^125/131I-IBA-CP was prepared in a typical radiochemical yield of about 65% (decay-corrected), radiochemical purity of more than 98%, and molar activity of 42 GBq/μmol at the end of synthesis. SPECT imaging revealed significantly higher uptake of ¹²⁵I-IBA-CP than of ¹²⁵I-ICP in the HER2-positive MDA-MB-453 tumors. Uptake in the HER2-negative MCF-7 tumors was much lower. Binding of ¹²⁵I-IBA-CP in the MDA-MB-453 tumors was blocked by coinjection with an excess amount of IBA-CP, but not by erlotinib. <b>Conclusion:</b> The radiolabeled HER2-selective inhibitor ^125/131I-IBA-CP is a promising probe for in vivo detection of HER2-positive tumors.