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.
Original language | English |
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Article number | 129088 |
Journal | Bioorganic and Medicinal Chemistry Letters |
Volume | 80 |
Number of pages | 5 |
ISSN | 0960-894X |
DOIs | |
Publication status | Published - 2023 |
Bibliographical note
Publisher Copyright:
© 2022 The Author(s)
- Breast cancer, Carbon-11, HER2, PET imaging, Radiolabeling, Tucatinib
Research areas
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