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Nat Commun. 2017 Jun 8;8:15761. doi: 10.1038/ncomms15761.

Synthesis and preliminary PET imaging of 11C and 18F isotopologues of the ROS1/ALK inhibitor lorlatinib.

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Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, USA.
Advion Inc., 30 Brown Road, Ithaca, New York 14850, USA.
Vanderbilt University, 1161 21st Avenue South, Nashville, Tennessee 37232, USA.
Pfizer Inc., Quantitative Medicine, Worldwide Research and Development, 1 Portland Street, Cambridge, Massachusetts 02139, USA.
Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, California 92121, USA.


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 11C- and 18F-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 11C-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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