Synthesis and in vivo evaluation of [11C]tucatinib for HER2-targeted PET imaging

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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. [11C]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 [11C]tucatinib is too lipophilic to be used as a tumor targeting PET tracer. Therefore, chemical modifications of [11C]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.

TidsskriftBioorganic and Medicinal Chemistry Letters
Antal sider5
StatusUdgivet - 2023

Bibliografisk note

Funding Information:
Daniel Dahan, Per Weihrauch, Jesper Jørgensen, and Holger J. Jensen are gratefully acknowledged for the production and supply of [ 11 C]CH 4 . This project was initiated by Vasko Kramer, Umberto M. Battisti, Andreas Kjaer and Matthias M. Herth. Tucatinib, and its trimethyl stannyl derivative were synthesized by Marius Müller. Radiolabeling was carried out by Vladimir Shalgunov. PET imaging was conducted by Lars Hvass and Jesper T. Jørgensen. Both the project and the submission of this article were supervised by Umberto M. Battisti, Andreas Kjaer, and Matthias M. Herth. This work was supported by the Danmarks Frie Forskningsfond (1032-00177B), the Lundbeck Foundation (grants R303-2018-3567, R278-2018-548), the Novo Nordisk Foundation, the Innovation Fund Denmark, Sygesikringen “danmark”, the Danish Cancer Society, Arvid Nilsson Foundation, the Neye Foundation, the Research Foundation of Rigshospitalet, the Danish National Research Foundation (grant 126), the Research Council of the Capital Region of Denmark, and the John and Birthe Meyer Foundation. Andreas Kjaer is a Lundbeck Foundation Professor.

Publisher Copyright:
© 2022 The Author(s)

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