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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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February 2, 2012

Fluorine NMR: Why Not?

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Posted by Derek

Fluorine NMR is underused in chemistry. Well, then again, maybe it's not, but it's one of those thing that just seems like it should have more uses than it does. (Here's a recent bookon the subject). Fluorine is a great NMR nucleus - all the F in the world is the same isotope, unless you're right next to a PET scanning facility - and the different compound show up over a very wide range of chemical shifts. You've got that going for you, coupling information, NOE, basically all your friends from proton NMR.

There's a pretty recent paper showing a good use of all these qualities (blogged about here at Practical Fragments as well). A group at Amgen reports on their work using fluorine NMR as a fragment-screening tool. They can take mixtures of 10 or 12 compounds at a time (because of all those different chemical shifts) and run the spectra with and without a target protein in the vial. If a fragment binds, its F peak broadens out (you can even get binding constants if you run at a few different concentrations). A simple overlay of the two spectra tells you immediately if you have hits. You don't need to have any special form of the protein, and you don't even need to run in deuterated solvents, since you're just ignoring protons altogether.

Interestingly, when they go on to try other assay techniques as follow-up, they find that the fluorines themselves aren't always a key part of the binding. Sometimes switching to the non-fluorinated version of the fragment gives you a better compound; sometimes it doesn't. The binding constants you get from the NMR, though, do compare very well to the ones from other assays.

The part I found most interesting was the intra-ligand NOE example. (That's also something that's been done in proton NMR, although it's not easy). They show a case where 19F ligands do get close enough to show the effect, and that a linked version of the two fragments does, as you'd hope, make a much more potent compound. That's the sort of thing that fragment people are always wanting to know - what fits next door to my hit? Can they be linked together? Fragment linking has its ups and downs, going back to the Abbott SAR-by-NMR days. That was a technique that never really panned out, as far as can be seen, but this is at least an experimentally easy way to give it a shot. (Of course, the chances of the fluorines on your ligands actually being pointed at each other is probably small, so that does cancel things out a bit).

Overall, it's a fun paper to read - well, allowing for my geeky interests, it is - and perhaps it'll lead a few more people to think of things that could be done with fluorine NMR in general. It's just sitting there, waiting to be used. . .

Comments (9) + TrackBacks (0) | Category: Analytical Chemistry | Drug Assays


1. RTW on February 2, 2012 1:45 PM writes...

I have always found Fluorine NMR to be interesting and useful, and often used it when I produced complex molecules containing the element. Where proton spectra might look very much alike from starting material to product, sometimes fluorine spectra was very different. I could often much more easily follow the course of a reaction via 18F NMR, when it wasn't so easy to do with other techniques.

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2. milkshake on February 2, 2012 2:29 PM writes...

I love fluorine as a very sensitive label for monitoring metastable intermediates in situ. You dont even need to run the reaction in a deuterated solvent, you just sample it into one, just enough to get a lock...

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3. DJ DrZ on February 2, 2012 3:42 PM writes...

The real problem with 19F NMR is that not everybody has a readily available 19F probe. Typically, people have a low field (think ~400MHz) BBO probe or a dedicated 19F probe typically used for polymers.
Thanks for reading our blog too!

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4. MILFshake on February 2, 2012 3:51 PM writes...

Can you use it in vivo?

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5. Algirdas on February 2, 2012 10:30 PM writes...

"Can you use it in vivo?"

Yes. It is nice - no background garbage obscuring peaks of interest. Search Pubmed for "fluorine nmr in vivo".

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6. Anonymous on February 3, 2012 6:26 AM writes...

Alceo Macchioni has done beautiful 19F,1H-NOE experiments

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7. dange82 on February 3, 2012 3:36 PM writes...

19F MRI seems like a potential option to me too.

I did quite a lot of work on hyperpolarised NMR and MRI but we never 'got round' to doing any MRI with 19F, only a few hyperpolarised 19F NMR measurements.

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8. MILFshake on February 4, 2012 1:20 AM writes...

Thanks nerds! As we used to say in the Army, love you mean it!

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9. DrSAR on February 7, 2012 4:35 PM writes...

Another neat use for in-vivo fluorine NMR is probing oxygenation (oxygen saturation in vivo tumours is still quite tricky to accomplish) and, also, people have looked at drugs: SR4554

The proximity to proton in resonance makes dual-resonance probe design a little tricky but in many other respects it's a lovely nucleus.

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