68Ga labeled Olmutinib: Design, synthesis, and evaluation of a novel PET EGFR probe

Hua Cheng; Liyan Bai; Xi Zhang; Wenfei Chen; Simin He; Yunqi Liu; Juan Wang; Shaoli Song

doi:10.1016/j.bioorg.2024.107987

⁶⁸Ga labeled Olmutinib: Design, synthesis, and evaluation of a novel PET EGFR probe

Bioorg Chem. 2024 Nov 22:153:107987. doi: 10.1016/j.bioorg.2024.107987. Online ahead of print.

Authors

Hua Cheng¹, Liyan Bai², Xi Zhang³, Wenfei Chen⁴, Simin He², Yunqi Liu⁵, Juan Wang⁶, Shaoli Song⁷

Affiliations

¹ Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, China; Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
² Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, China.
³ Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
⁴ The Fifth Affiliated Hospital of Xinjiang Medical University, Xinjiang Medical University, Xinjiang 830011, China.
⁵ School of Medicine, Shanghai University, Shanghai 200444, China.
⁶ School of Medicine, Shanghai University, Shanghai 200444, China. Electronic address: juanw@shu.edu.cn.
⁷ Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, China; Shanghai Key Laboratory of Bioactive Small Molecules, Fudan University, Shanghai, China. Electronic address: shaoli_song@fudan.edu.cn.

PMID: 39579551
DOI: 10.1016/j.bioorg.2024.107987

Abstract

Radiolabeled tyrosine kinase inhibitors (TKIs) offer a promising approach for molecular imaging of EGFR-positive cancers. Despite the development of various EGFR small-molecule probes, none of the ⁶⁸Ga-labeled small-molecule probes based on the chelator DOTA have shown tumor-specific uptake. To address this challenge, we selected Olmutinib, a third-generation EGFR covalent inhibitor, as a PET imaging tracer for EGFR-positive tumors. We synthesized the precursor DOTA-Olmutinib through a five-step process and subsequently radiolabeled it with ⁶⁸Ga to prepare ⁶⁸Ga-DOTA-Olmutinib. ⁶⁸Ga-DOTA-Olmutinib displayed moderate lipophilicity (log P = 0.85) and exhibited high stability in vitro and in vivo. Western blot analysis was used to detect the level of EGFR in multiple tumor cells. In cell uptake experiments, ⁶⁸Ga-DOTA-Olmutinib exhibited enhanced uptake specifically in tumor cells with a higher level of EGFR supporting it as an EGFR-specific tracer. Additionally, PET/CT imaging with ⁶⁸Ga-DOTA-Olmutinib showed significant tumor uptake at 60 min with 4 % ID/g post-injection, marking a breakthrough, though the uptake is not yet ideal. Overall, our results suggest that ⁶⁸Ga-labeled Olmutinib holds promise as a potential PET tracer for detecting EGFR-positive cancers.

Keywords: (68)Ga-labeled; Olmutinib; PET; Radioligands; Radiology imaging; Synthesis; Tracer.