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

Mueller, Marius; Shalgunov, Vladimir; Hvass, Lars; Jorgensen, Jesper T.; Kramer, Vasko; Staudt, Markus; Battisti, Umberto Maria; Kjaer, Andreas; Herth, Matthias M.

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-brainbarrier (BBB) penetrant HER2 PET imaging probe based on tucatinib. [11C]tucatinib was synthesized via a Stillecoupling 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.

Más información

Título según WOS: ID WOS:000905164700005 Not found in local WOS DB
Título de la Revista: BIOORGANIC MEDICINAL CHEMISTRY LETTERS
Volumen: 80
Editorial: PERGAMON-ELSEVIER SCIENCE LTD
Fecha de publicación: 2023
DOI:

10.1016/j.bmcl.2022.129088

Notas: ISI