Development and Preclinical Characterization of [18F]H3-2406 and [18F]H3-2407 for Positron Emission Tomography Imaging of the Histamine Subtype-3 Receptor

  • J Med Chem. 2025 Aug 14;68(15):15372-15385. doi: 10.1021/acs.jmedchem.4c02924.
Zhendong Song  1 ,  Yinlong Li  1 ,  Kenneth Dahl  2  3 ,  Zhenkun Sun  4 ,  Jiahui Chen  1 ,  Xin Zhou  1 ,  Yabiao Gao  1 ,  Jian Rong  1 ,  Chunyu Zhao  1 ,  Katherine Yuan  1 ,  Ahmad F Chaudhary  1 ,  Jimmy S Patel  1  5 ,  Thomas L Collier  1 ,  Chongzhao Ran  6 ,  Kim S Muehlfenzl  7 ,  Achi Haider  1 ,  Charles S Elmore  7 ,  Magnus Schou  2  3 ,  Steven H Liang  1
Affiliations
  • 1. Department of Radiology and Imaging Sciences, Emory University, 1364 Clifton Road, Atlanta, Georgia 30322, United States.
  • 2. PET Science Centre, Precision Medicine and Biosamples, Oncology R&D, AstraZeneca, Karolinska Institutet, Stockholm 17176, Sweden.
  • 3. Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet and Stockholm County Council, Stockholm 17176, Sweden.
  • 4. Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, Georgia 30322, United States.
  • 5. Department of Radiation Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia 30322, United States.
  • 6. Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, United States.
  • 7. Early Chemical Development, Pharmaceutical Sciences, R&D, AstraZeneca Pharmaceuticals, Gothenburg 43183, Sweden.
PMID: 40665705 DOI: 10.1021/acs.jmedchem.4c02924
Abstract

The histamine subtype 3 receptor (H3R) is a G protein-coupled receptor involved in various central nervous system (CNS) disorders. We herein describe the identification and preclinical evaluation of two H3R antagonists: compounds 3 (H3-2406, Ki = 2.87 nM) and 4 (H3-2407, Ki = 3.15 nM) as potential PET radioligands. Both were radiolabeled with fluorine-18 using a copper-mediated method. Among them, [18F]3 showed high radiochemical yield (32.4%), molar activity (103 GBq/μmol), and moderate brain uptake (SUV = 2.4), with regional distribution matching known H3R expression. [18F]3 also exhibited favorable pharmacokinetics, high metabolic stability and negligible efflux by transporter proteins. However, relatively high cerebellar uptake, along with dedicated blocking studies, suggested off-target binding to the sigma-1 receptor, likely due to limited selectivity over sigma-1 (69-fold). These findings highlight [18F]3 as a promising lead for H3R imaging, with future work aimed at improving its selectivity and minimizing off-target binding.

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