期刊
NATURE COMMUNICATIONS
卷 8, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms15761
关键词
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资金
- NIH career development award from the National Institute on Drug Abuse [DA038000]
- National Institute on Ageing of the NIH [R01AG054473]
- Pfizer Inc.
Lorlatinib (PF-06463922) is a next-generation small-molecule inhibitor of the orphan receptor tyrosine kinase c-ros oncogene 1 (ROS1), which has a kinase domain that is physiologically related to anaplastic lymphoma kinase (ALK), and is undergoing Phase I/II clinical trial investigations for non-small cell lung cancers. An early goal is to measure the concentrations of this drug in brain tumour lesions of lung cancer patients, as penetration of the blood-brain barrier is important for optimal therapeutic outcomes. Here we prepare both C-11- and F-18-isotopologues of lorlatinib to determine the biodistribution and whole-body dosimetry assessments by positron emission tomography (PET). Non-traditional radiolabelling strategies are employed to enable an automated multistep C-11-labelling process and an iodonium ylide-based radiofluorination. Carbon-11-labelled lorlatinib is routinely prepared with good radiochemical yields and shows reasonable tumour uptake in rodents. PET imaging in non-human primates confirms that this radiotracer has high brain permeability.
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