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

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 ()
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Thomas Lee Collier: Massachusetts General Hospital and Harvard Medical School
Marc D. Normandin: Massachusetts General Hospital and Harvard Medical School
Nickeisha A. Stephenson: Massachusetts General Hospital and Harvard Medical School
Eli Livni: Massachusetts General Hospital and Harvard Medical School
Steven H. Liang: Massachusetts General Hospital and Harvard Medical School
Dustin W. Wooten: Massachusetts General Hospital and Harvard Medical School
Shadi A. Esfahani: Massachusetts General Hospital and Harvard Medical School
Michael G. Stabin: Vanderbilt University
Umar Mahmood: Massachusetts General Hospital and Harvard Medical School
Jianqing Chen: Pfizer Inc., Quantitative Medicine, Worldwide Research and Development
Wei Wang: Pfizer Worldwide Research and Development
Kevin Maresca: Pfizer Inc., Quantitative Medicine, Worldwide Research and Development
Rikki N. Waterhouse: Pfizer Inc., Quantitative Medicine, Worldwide Research and Development
Georges El Fakhri: Massachusetts General Hospital and Harvard Medical School
Paul Richardson: Pfizer Worldwide Research and Development
Neil Vasdev: Massachusetts General Hospital and Harvard Medical School

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/ncomms15761

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