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.
Highlights
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
Over a dozen ALK fusion partners have been identified in several cancer types1–4, and this has led to clinical translation and United States Food and Drug Administration approval of ALK inhibitors5 as a first-line treatment for ALK-positive lung cancer patients
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 and inhibits ALK6. This orally available, ATP-competitive inhibitor has shown excellent therapeutic potential against ROS1-driven fusion cancers, and significantly improved inhibitory activity compared with the first-generation-approved tyrosine kinase inhibitors (TKIs) including the ALK/mesenchymal–epithelial transition factor/ROS inhibitor, crizotinib (Xalkori)7, as well as next-generation ALK and ALK/ROS1 inhibitors, ceritinib and alectinib8,9
Summary
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. This lack of effort is partially attributed to the additional challenges of imaging intracellular targets, compared to highdensity receptor and enzyme targets at the extracellular domain, and competition at binding sites with high intracellular levels of ATP These difficulties are further exacerbated by the challenging radiochemistry required to prepare isotopologues of the structurally complex potent and selective TKIs. A PET radiotracer for ALK could aid many ongoing clinical trials with ALK-targeted therapeutics by indicating the success and extent of engagement by ALK in the periphery and central nervous system, as well as for occupancy studies to assess dose–response and to understand the PK properties of a labelled drug. We synthesize carbon-11 (11C; b þ , t1⁄2 1⁄4 20.4 min) and fluorine-18 (18F; b þ , t1⁄2 1⁄4 109.7 min)labelled isotopologues of lorlatinib and carry out preliminary biodistribution and PET imaging using [11C]lorlatinib in tumour-bearing rodents and non-human primates (NHPs)
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