• Thomas Lee Collier, Marc D Normandin, Nickeisha A Stephenson, Eli Livni, Steven H Liang, Dustin W Wooten, Shadi A Esfahani, Michael G Stabin, Umar Mahmood, Jianqing Chen, Wei Wang, Kevin Maresca, Rikki N Waterhouse, Georges El Fakhri, Paul Richardson, and Neil Vasdev.
• Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, USA.
• Nat Commun. 2017 Jun 8; 8: 15761.

AbstractLorlatinib (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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