Fluorescence activation mechanism and imaging of drug permeation with new sensors for smoking-cessation ligands

Essential revisions:

Please make changes to the text for clarity and answer the individual small questions raised in the reviewers' recommendations below. Also, several reviewers agreed that the impact and interest of the paper for the audience could be broadened by adding a little material to the discussion about how analogous tools may be useful beyond the explicit case of nicotine addiction.

The revised Discussion adds the explicit statement:

“The iDrugSnFR paradigm will be useful beyond the explicit case of nicotine addiction, with application to other exogenous neural drugs.”

Reviewer #2 (Recommendations for the authors):

Great read, this is a beautiful piece of work. My only concern is that the paper covers such a broad swath of disciplines that it might be better with additional background? Biosensor people know remarkably little about target engagement issues in drug discover, pharmacologists are only vaguely aware of biosensors, and medicinal chemists are on a different planet. Is there a way to frame the bigger picture beyond nicotine addiction? It's so easy to see how this sort of approach could be used in SAR in different drug discovery campaigns for example.

Amusingly, none of the authors have ever taken a formal course in the disciplines noted: biosensors, drug discovery, pharmacology, medicinal chemistry, or (not mentioned) pharmacokinetics. Lightheartedly, we note that none of us are known to suffer from imposter syndrome.

More seriously, we have presented 2021 SfN abstracts on related biosensors for opioids, SSRIs, and rapidly acting antidepressants. When those papers are submitted and published, we hope to verify Reviewer 2’s prediction. Meanwhile, the revised Discussion ends with the Editor’s suggested statement:

“The iDrugSnFR paradigm will be useful beyond the explicit case of nicotine addiction, with application to other exogenous neural drugs.”