Format

Send to

Choose Destination
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.

Author information

1
Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, USA.
2
Advion Inc., 30 Brown Road, Ithaca, New York 14850, USA.
3
Vanderbilt University, 1161 21st Avenue South, Nashville, Tennessee 37232, USA.
4
Pfizer Inc., Quantitative Medicine, Worldwide Research and Development, 1 Portland Street, Cambridge, Massachusetts 02139, USA.
5
Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, California 92121, USA.

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.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center