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.