2. Academic Validation
  3. Identification and Profiling of a Selective and Brain Penetrant Radioligand for in Vivo Target Occupancy Measurement of Casein Kinase 1 (CK1) Inhibitors

Identification and Profiling of a Selective and Brain Penetrant Radioligand for in Vivo Target Occupancy Measurement of Casein Kinase 1 (CK1) Inhibitors

  • ACS Chem Neurosci. 2017 Sep 20;8(9):1995-2004. doi: 10.1021/acschemneuro.7b00155.
Travis T Wager 1,  Paul Galatsis 1,  Ramalakshmi Y Chandrasekaran 1 2,  Todd W Butler 1 2,  Jianke Li 1 2,  Lei Zhang 1,  Scot Mente 1,  Chakrapani Subramanyam 1 2,  Shenping Liu 1,  Angela C Doran 3,  Cheng Chang 3,  Katherine Fisher 4,  Sarah Grimwood 4,  Joseph R Hedde 4,  Michael Marconi 4,  Klaas Schildknegt 5
Affiliations

Affiliations

  • 1 Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development , 1 Portland, Cambridge, Massachusetts 02139, United States.
  • 2 Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development , 558 Eastern Point Rd, Groton, Connecticut 06340, United States.
  • 3 Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide Research and Development , 558 Eastern Point Rd, Groton, Connecticut 06340, United States.
  • 4 Internal Medicine Research Unit, Pfizer Worldwide Research and Development , 1 Portland, Cambridge, Massachusetts 02139, United States.
  • 5 Chemical Research and Development, Pharmaceutical Sciences, Pfizer Worldwide Research and Development , 558 Eastern Point Rd, Groton, Connecticut 06340, United States.
PMID: 28609096 DOI: 10.1021/acschemneuro.7b00155
Abstract

To enable the clinical development of our CNS Casein Kinase 1 delta/epsilon (CK1δ/ε) inhibitor project, we investigated the possibility of developing a CNS positron emission tomography (PET) radioligand. For this effort, we focused our design and synthesis efforts on the initial CK1δ/ε inhibitor HTS hits with the goal of identifying a compound that would fulfill a set of recommended PET ligand criteria. We identified [3H]PF-5236216 (9) as a tool ligand that meets most of the key CNS PET attributes including high CNS MPO PET desirability score and kinase selectivity, CNS penetration, and low nonspecific binding. We further used [3H]-9 to determine the binding affinity for PF-670462, a literature CK1δ/ε inhibitor tool compound. Lastly, [3H]-9 was used to measure in vivo target occupancy (TO) of PF-670462 in mouse and correlated TO with CK1δ/ε in vivo pharmacology (circadian rhythm modulation).

Keywords

CK1; CK1δ/ε; Casein kinase 1; circadian rhythm; delta; epsilon; kinase inhibitor; radiotracer; target occupancy.

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