Brain Penetration of the ROS1/ALK Inhibitor Lorlatinib Confirmed by PET

• Type of Material: Article
• Authors: T. Lee Collier, Massachusetts General Hospital; Kevin P. Maresca, Pfizer Inc.; Marc D. Normandin, Massachusetts General Hospital; Paul Richardson, Pfizer Inc.; Timothy J. McCarthy, Pfizer Inc.; Steven Huan Liang, Emory University; Rikki N. Waterhouse, Pfizer Inc.; Neil Vasdev, Massachusetts General Hospital
• Language: English
• Date: 2017-10-20
• Publisher: SAGE
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2017
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1177/1536012117736669
• Title of Journal or Parent Work: Molecular Imaging
• Volume: 16
• Start Page: 1536012117736669
• End Page: 1536012117736669
• Grant/Funding Information: N.V. thanks Pfizer and the National Institute on Ageing of the NIH for funding (R01AG054473). S.H.L. is a recipient of an NIH career development award (DA038000) and an Early Career Award in Chemistry of Drug Abuse and Addiction (ECHEM, DA043507) from the National Institute on Drug Abuse.
• Keywords: Macaca mulatta; Lactams, Macrocyclic; Anaplastic Lymphoma Kinase; fluorine-18; Animals; Pyrazoles; ALK; carbon-11; Humans; lorlatinib; Proto-Oncogene Proteins; Protein-Tyrosine Kinases; Protein Kinase Inhibitors; Positron-Emission Tomography; Receptor Protein-Tyrosine Kinases; ROS1; Brain; positron emission tomography; Lactams; Aminopyridines
• Research Categories: Chemistry, Biochemistry; Chemistry, Radiation

Abstract

The Massachusetts General Hospital Radiochemistry Program, in collaboration with Pfizer, has developed unique 11C and 18F-labeling strategies to synthesize isotopologs of lorlatinib (PF-06463922) which is undergoing phase III clinical trial investigations for treatment of non-small-cell lung cancers with specific molecular alterations. A major goal in cancer therapeutics is to measure the concentrations of this drug in the brain metastases of patients with lung cancer, and penetration of the blood–brain barrier is important for optimal therapeutic outcomes. Our recent publication in Nature Communications employed radiolabeled lorlatinib and positron emission tomography (PET) studies in preclinical models including nonhuman primates (NHPs) that demonstrated high brain permeability of this compound. Our future work with radiolabeled lorlatinib will include advanced PET evaluations in rodent tumor models and normal NHPs with the goal of clinical translation.