Development and Initial Characterization of the First 18F-CXCR2-Targeting Radiotracer for PET Imaging of Neutrophils

  • J Med Chem. 2024 Apr 25;67(8):6327-6343. doi: 10.1021/acs.jmedchem.3c02285.
Philipp Spatz  1 ,  Xinyu Chen  2  3 ,  Kora Reichau  1 ,  Max E Huber  4 ,  Saskia Mühlig  3 ,  Yohji Matsusaka  3 ,  Matthias Schiedel  4  5 ,  Takahiro Higuchi  3  6 ,  Michael Decker  1
Affiliations
  • 1. Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, University of Würzburg, Würzburg 97074, Germany.
  • 2. Nuclear Medicine, Faculty of Medicine, University of Augsburg, Augsburg 86156, Germany.
  • 3. Department of Nuclear Medicine and Comprehensive Heart Failure Center, University Hospital Würzburg, Würzburg 97080, Germany.
  • 4. Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen 91058, Germany.
  • 5. Pharmaceutical and Medicinal Chemistry, Institute of Medicinal and Pharmaceutical Chemistry, Technical University of Braunschweig, Braunschweig 38106, Germany.
  • 6. Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-0082, Japan.
PMID: 38570909 DOI: 10.1021/acs.jmedchem.3c02285
Abstract

The interleukin-8 receptor beta (CXCR2) is a highly promising target for molecular imaging of inflammation and inflammatory diseases. This is due to its almost exclusive expression on neutrophils. Modified fluorinated ligands were designed based on a squaramide template, with different modification sites and synthetic strategies explored. Promising candidates were then tested for affinity to CXCR2 in a NanoBRET competition assay, resulting in tracer candidate 16b. As direct 18F-labeling using established tosyl chemistry did not yield the expected radiotracer, an indirect labeling approach was developed. The radiotracer [18F]16b was obtained with a radiochemical yield of 15% using tert-butyl (S)-3-(tosyloxy)pyrrolidine carboxylate and a pentafluorophenol ester. The subsequent time-dependent uptake of [18F]16b in CXCR2-negative and CXCR2-overexpressing human embryonic kidney cells confirmed the radiotracer's specificity. Further studies with human neutrophils revealed its diagnostic potential for functional imaging of neutrophils.

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