Synthesis and in vivo evaluation of [11C]tucatinib for HER2-targeted PET imaging. (15th January 2023)

• Record Type: Journal Article
• Authors: Müller, Marius; Shalgunov, Vladimir; Hvass, Lars; Jørgensen, Jesper T.; Kramer, Vasko; Staudt, Markus; Battisti, Umberto Maria; Kjaer, Andreas; Herth, Matthias M.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 80(2023)
• Publication Date: 2023-01-15
• Subjects: Breast cancer -- HER2 -- Tucatinib -- PET imaging -- Radiolabeling -- Carbon-11; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2022.129088
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: [ 11 C]tucatinib was designed and synthesized as a HER2 PET imaging agent The compound was obtained in a 12 steps synthetic route [ 11 C]tucatinib was obtained in good radiochemical yield and high radiochemical purity [ 11 C]tucatinib showed high liver and intestinal uptake and low tumor uptake Modifications of [ 11 C]tucatinib are required to obtain a successful HER2 PET tracer Abstract: Tucatinib is a selective human epidermal growth factor receptor 2 (HER2) tyrosine kinase inhibitor approved by the U.S. Food and Drug Administration (FDA) in April 2020 for HER2-positive lesions in metastatic breast cancer patients, including CNS metastases. In this article, we attempted to develop the first small molecule, blood–brain-barrier (BBB) penetrant HER2 PET imaging probe based on tucatinib. [ 11 C]tucatinib was synthesized via a Stille-coupling from the respective trimethylstannyl precursor and its biodistribution was evaluated in NMRI nude mice bearing HER2-overexpressing human ovarian cancer cells (SKOV-3). No significant tumor accumulation was observed despite its high affinity for HER-2 receptors (IC50 = 6.9 nM). High liver and intestinal uptake indicate that [ 11 C]tucatinib is too lipophilic to be used as a tumor targeting PET tracer. Therefore, chemical modifications of [ 11 C]tucatinib are needed to increase the polarity for tumor imaging. Tucatinib as an FDA approved drug is still an interesting platform to develop the first small molecule HER2-selective PET tracer. The study highlights the differences between a drug, which needs to be effective, and an imaging agent, which is dependent on contrast.