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

Publisher: Elsevier Country of Publication: United States NLM ID: 1303703 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2120 (Electronic) Linking ISSN: 00452068 NLM ISO Abbreviation: Bioorg Chem Subsets: MEDLINE

Publication: Amsterdam : Elsevier
Original Publication: New York, London, Academic Press.

Drug Design* ; ErbB Receptors*/antagonists & inhibitors ; ErbB Receptors*/metabolism ; Gallium Radioisotopes*/chemistry ; Positron-Emission Tomography*/methods; Animals ; Humans ; Mice ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Mice, Nude ; Molecular Structure ; Neoplasms, Experimental/diagnostic imaging ; Neoplasms, Experimental/drug therapy ; Neoplasms, Experimental/pathology ; Neoplasms, Experimental/metabolism ; Protein Kinase Inhibitors/chemical synthesis ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/chemistry ; Radiopharmaceuticals/chemical synthesis ; Radiopharmaceuticals/chemistry ; Radiopharmaceuticals/pharmacology ; Structure-Activity Relationship ; Tissue Distribution ; Piperazines/chemistry ; Piperazines/pharmacology ; Pyrimidines/chemistry ; Pyrimidines/pharmacology

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 ⁶⁸ Ga-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 ⁶⁸ Ga to prepare ⁶⁸ Ga-DOTA-Olmutinib. ⁶⁸ Ga-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, ⁶⁸ Ga-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 ⁶⁸ Ga-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 ⁶⁸ Ga-labeled Olmutinib holds promise as a potential PET tracer for detecting EGFR-positive cancers.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024. Published by Elsevier Inc.)

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

EC 2.7.10.1 (EGFR protein, human)
EC 2.7.10.1 (ErbB Receptors)
0 (Gallium Radioisotopes)
98B30EPP5S (Gallium-68)
0 (Protein Kinase Inhibitors)
0 (Radiopharmaceuticals)
CHL9B67L95 (olmutinib)
0 (Piperazines)
0 (Pyrimidines)

Date Created: 20241123 Date Completed: 20241203 Latest Revision: 20241211

20241211

10.1016/j.bioorg.2024.107987

39579551