Structure-Activity Relationship of Nerve-Highlighting Fluorophores

Summer Gibbs, Yang Xie, Haley L. Goodwill, Khaled A. Nasr, Yoshitomo Ashitate, Victoria J. Madigan, Tiberiu M. Siclovan, Maria Zavodszky, Cristina A. Tan Hehir, John V. Frangioni

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18 Scopus citations

Abstract

Nerve damage is a major morbidity associated with numerous surgical interventions. Yet, nerve visualization continues to challenge even the most experienced surgeons. A nerve-specific fluorescent contrast agent, especially one with near-infrared (NIR) absorption and emission, would be of immediate benefit to patients and surgeons. Currently, there are only three classes of small molecule organic fluorophores that penetrate the blood nerve barrier and bind to nerve tissue when administered systemically. Of these three classes, the distyrylbenzenes (DSBs) are particularly attractive for further study. Although not presently in the NIR range, DSB fluorophores highlight all nerve tissue in mice, rats, and pigs after intravenous administration. The purpose of the current study was to define the pharmacophore responsible for nerve-specific uptake and retention, which would enable future molecules to be optimized for NIR optical properties. Structural analogs of the DSB class of small molecules were synthesized using combinatorial solid phase synthesis and commercially available building blocks, which yielded more than 200 unique DSB fluorophores. The nerve-specific properties of all DSB analogs were quantified using an ex vivo nerve-specific fluorescence assay on pig and human sciatic nerve. Results were used to perform quantitative structure-activity relationship (QSAR) modeling and to define the nerve-specific pharmacophore. All DSB analogs with positive ex vivo fluorescence were tested for in vivo nerve specificity in mice to assess the effect of biodistribution and clearance on nerve fluorescence signal. Two new DSB fluorophores with the highest nerve to muscle ratio were tested in pigs to confirm scalability.

Original languageEnglish (US)
Article numbere73493
JournalPLoS One
Volume8
Issue number9
DOIs
Publication statusPublished - Sep 9 2013

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ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Gibbs, S., Xie, Y., Goodwill, H. L., Nasr, K. A., Ashitate, Y., Madigan, V. J., ... Frangioni, J. V. (2013). Structure-Activity Relationship of Nerve-Highlighting Fluorophores. PLoS One, 8(9), [e73493]. https://doi.org/10.1371/journal.pone.0073493