Radioiodinated Small-Molecule Tyrosine Kinase Inhibitor for HER2-Selective SPECT Imaging

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 (I-IBA-CP) of the HER2-selective inhibitor CP724,714 was prepared and evaluated in HER2-positive or -negative subcutaneous human breast cancer xenografts. The CP724,714 analog IBA-CP was synthesized and assayed for its inhibitory activities against HER2 and 6 other tyrosine kinases.I-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 I-IBA-CP to its HER2 kinase target, was assessed in different cell lines. In vivo small-animalI-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 I-IBA-CP toward HER2 in vitro and in vivo. Additionally,I-ICP was prepared by direct radioiodination of CP724,714 for comparison with I-IBA-CP. 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. I-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 ofI-IBA-CP than of I-ICP in the HER2-positive MDA-MB-453 tumors. Uptake in the HER2-negative MCF-7 tumors was much lower. Binding ofI-IBA-CP in the MDA-MB-453 tumors was blocked by coinjection with an excess amount of IBA-CP, but not by erlotinib. The radiolabeled HER2-selective inhibitorI-IBA-CP is a promising probe for in vivo detection of HER2-positive tumors.

Development and Preclinical Evaluation of Radiolabeled Covalent G12C-Specific Inhibitors for Direct Imaging of the Oncogenic KRAS Mutant

“…Both tracers were successfully prepared with considerable radiolabeling yields and molar activities. The calculated log P values and stability of [ 131 I]­I-ARS-1620 and [ 18 F]­F-ARS-1620 were comparable to those of successful imaging probes. − Although [ 131 I]­I-ARS-1620 and [ 18 F]­F-ARS-1620 have similar binding modes and key interactions to ARS-1620, [ 131 I]­I-ARS-1620 may have a more favorable conformation than [ 18 F]­F-ARS-1620 because of acquisition of an additional interaction with ARG-68. From the perspective of binding energy, it was more difficult for [ 18 F]­F-ARS-1620 to covalently bind Cys-12 in the KRAS G12C protein.…”

Radioiodinated Portable Albumin Binder as a Versatile Agent for in Vivo Imaging with Single-Photon Emission Computed Tomography

“…[ 131 I]IBA, compared with EB dyes, has several eminent advantages: mild labeling conditions, simple operational processes, and stable chemical structure, and no obvious deiodination is observed in vivo and in vitro experiments, which agrees well with the previous studies. 18,19,28 In contrast, as shown in Figure S15, [ 131 I]EB has shortage instability, which degenerates the images seriously. Tedious purification processes were always bottlenecks restricting the next application of drug candidates.…”

Radioiodinated progesterone derivative for progesterone receptor targeting with enhanced nucleus uptake via phenylboronic acid conjugation

“…The mice were sacrificed at 30 minutes and 1 hour postinjection. Blood, urine, and liver samples were collected and treated using previously published methods . The blood was immediately centrifuged at 13 000 rpm.…”