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

Author

Listed:
  • Thomas Lee Collier

    (Massachusetts General Hospital and Harvard Medical School
    Advion Inc.)

  • Marc D. Normandin

    (Massachusetts General Hospital and Harvard Medical School)

  • Nickeisha A. Stephenson

    (Massachusetts General Hospital and Harvard Medical School
    Present address: Department of Chemistry, University of the West Indies, Mona, Kingston 7, Jamaica)

  • 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
    Present address: Waterhouse Imaging and Biomarker Consultants, 208 Candia Road, Chester, New Hampshire 03036, USA)

  • 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)

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.

Suggested Citation

  • 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 & Ke, 2017. "Synthesis and preliminary PET imaging of 11C and 18F isotopologues of the ROS1/ALK inhibitor lorlatinib," Nature Communications, Nature, vol. 8(1), pages 1-12, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15761
    DOI: 10.1038/ncomms15761
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    Cited by:

    1. Jian Rong & Ahmed Haider & Troels E. Jeppesen & Lee Josephson & Steven H. Liang, 2023. "Radiochemistry for positron emission tomography," Nature Communications, Nature, vol. 14(1), pages 1-23, December.

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