Synthesis and preliminary PET imaging of <sup>11</sup>C and <sup>18</sup>F isotopologues of the ROS1/ALK inhibitor lorlatinib.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 28594000.
- Also identified by DOI 10.1038/ncomms15761 and PMC identifier 5472746.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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 <sup>11</sup>C- and <sup>18</sup>F-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 <sup>11</sup>C-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.
Medical subject headings
- Carbon Radioisotopes
- Fluorine Radioisotopes
- Lactams, Macrocyclic
- Positron-Emission Tomography