Imaging Leucine-Rich Repeat Kinase 2 In Vivo with 18F-Labeled Positron Emission Tomography Ligand

  • J Med Chem. 2022 Oct 18. doi: 10.1021/acs.jmedchem.2c00551.
Zhen Chen  1  2 ,  Jiahui Chen  1 ,  Laigao Chen  3 ,  Chi-Hyeon Yoo  4 ,  Jian Rong  1 ,  Hualong Fu  1 ,  Tuo Shao  1 ,  Karen Coffman  5 ,  Stefanus J Steyn  6 ,  April T Davenport  7 ,  James B Daunais  7 ,  Ahmed Haider  1 ,  Lee Collier  1 ,  Lee Josephson  1 ,  Hsiao-Ying Wey  4 ,  Lei Zhang  8 ,  Steven H Liang  1
Affiliations
  • 1. Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, Massachusetts 02114, United States.
  • 2. Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources, College of Chemical Engineering, Jiangsu Provincial Key Lab for the Chemistry and Utilization of Agro-Forest Biomass, Nanjing Forestry University, Nanjing 210037 Jiangsu, China.
  • 3. Digital Medicine & Translational Imaging, Early Clinical Development, Pfizer Inc., Cambridge, Massachusetts 02139, United States.
  • 4. Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, United States.
  • 5. Internal Medicine Medicinal Chemistry, Pfizer Inc., Groton, Connecticut 06340, United States.
  • 6. Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Cambridge, Massachusetts 02139, United States.
  • 7. Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston Salem, North Carolina 27157, United States.
  • 8. Medicine Design, Internal Medicine Medicinal Chemistry, Pfizer Inc., Cambridge, Massachusetts 02139, United States.
PMID: 36256881 DOI: 10.1021/acs.jmedchem.2c00551
Abstract

Leucine-rich repeat kinase 2 (LRRK2) has been demonstrated to be closely involved in the pathogenesis of Parkinson's disease (PD), and pharmacological blockade of LRRK2 represents a new opportunity for therapeutical treatment of PD and Other related neurodegenerative conditions. The development of an LRRK2-specific positron emission tomography (PET) ligand would enable a target occupancy study in vivo and greatly facilitate LRRK2 drug discovery and clinical translation as well as provide a molecular imaging tool for studying physiopathological changes in neurodegenerative diseases. In this work, we present the design and development of compound 8 (PF-06455943) as a promising PET radioligand through a PET-specific structure-activity relationship optimization, followed by comprehensive pharmacology and ADME/neuroPK characterization. Following an efficient 18F-labeling method, we have confirmed high brain penetration of [18F]8 in nonhuman primates (NHPs) and validated its specific binding in vitro by autoradiography in postmortem NHP brain tissues and in vivo by PET imaging studies.

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