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

Area of Science:

• Radiochemistry and Molecular Imaging
• Oncology Drug Development

Background:

• Tucatinib is an FDA-approved HER2 tyrosine kinase inhibitor for HER2-positive metastatic breast cancer, including CNS metastases.
• Developing a small molecule, blood-brain-barrier (BBB) penetrant PET imaging probe for HER2 is a significant unmet need.

Purpose of the Study:

• To synthesize and evaluate the first small molecule HER2-selective PET imaging probe based on tucatinib.
• To assess the biodistribution and tumor-targeting potential of [11C]tucatinib in vivo.

Main Methods:

• Synthesis of [11C]tucatinib via Stille-coupling from a trimethylstannyl precursor.
• Biodistribution studies in NMRI nude mice bearing HER2-overexpressing SKOV-3 human ovarian cancer cells.

Main Results:

• Successful synthesis of [11C]tucatinib.
• No significant tumor accumulation was observed, despite tucatinib's high HER2 affinity (IC50 = 6.9 nM).
• High uptake in the liver and intestines indicated excessive lipophilicity, unsuitable for PET tumor imaging.

Conclusions:

• The tucatinib-based PET tracer, [11C]tucatinib, is too lipophilic for effective tumor imaging.
• Chemical modifications are required to increase polarity for potential use as a HER2-selective PET tracer.
• Tucatinib remains a promising scaffold for developing HER2-selective PET imaging agents, highlighting the distinct requirements for drugs versus imaging agents.