Revisiting PFA-mediated tissue fixation chemistry: FixEL enables trapping of small molecules in the brain to visualize their distribution changes

Hiroshi Nonaka, Takeharu Mino, Seiji Sakamoto, Jae Hoon Oh, Yu Watanabe, Mamoru Ishikawa, Akihiro Tsushima, Kazuma Amaike, Shigeki Kiyonaka, Tomonori Tamura, A. Radu Aricescu, Wataru Kakegawa, Eriko Miura, Michisuke Yuzaki, Itaru Hamachi

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Various small molecules have been used as functional probes for tissue imaging in medical diagnosis and pharmaceutical drugs for disease treatment. The spatial distribution, target selectivity, and diffusion/excretion kinetics of small molecules in structurally complicated specimens are critical for function. However, robust methods for precisely evaluating these parameters in the brain have been limited. Herein, we report a new method termed “fixation-driven chemical cross-linking of exogenous ligands (FixEL),” which traps and images exogenously administered molecules of interest (MOIs) in complex tissues. This method relies on protein-MOI interactions and chemical cross-linking of amine-tethered MOI with paraformaldehyde used for perfusion fixation. FixEL is used to obtain images of the distribution of the small molecules, which addresses selective/nonselective binding to proteins, time-dependent localization changes, and diffusion/retention kinetics of MOIs such as the scaffold of PET tracer derivatives or drug-like small molecules.

Original languageEnglish
Pages (from-to)523-540
Number of pages18
JournalChem
Volume9
Issue number2
DOIs
Publication statusPublished - 2023 Feb 9

Keywords

  • diffusion kinetics in brain
  • drug distribution
  • drug target engagement
  • hydrogel-tissue chemistry
  • ligand-protein interaction
  • molecular imaging
  • nanobody
  • neurotransmitter receptors
  • SDG3: Good health and well-being

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry
  • Environmental Chemistry
  • Chemical Engineering(all)
  • Biochemistry, medical
  • Materials Chemistry

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