Some like it hot

Tonight I am happy to host my former student, Ben Rotstein. Ben is currently doing a postdoc at Harvard Medical School. I caught up with Ben in Boston a couple of weeks ago and was really glad that he agreed to write a guest post about his research, which I find not only fascinating, but also very applicable in the real world. Here is what Ben wrote:

“As my time conducting graduate research in Andrei’s lab was coming to an end, I was considering what sort of work I wanted to do in a postdoc and the idea of translational research, where I could apply the skills I had developed in organic chemistry to problems in other fields, strongly appealed to me. It’s no wonder then that I leapt at the opportunity to join Dr. Neil Vasdev’s nascent radiochemistry group in Boston, despite at the time having little familiarity with radioactivity or positron emission tomography (PET). Fortunately, Neil and my colleagues here took the time to teach me about these things, and I can now tell you about some exciting work that we have recently published.

Carbon-11 along with fluorine-18 is a mainstay of PET radioisotopes suitable for small molecule labeling. With a half-life of only about 20.4 minutes, any radiochemistry using this isotope is a bit of a race against the clock, especially if there is an imaging study planned for the product. Most radiolabeling with carbon-11 uses [11C]methyl iodide or triflate to make methyl ethers, esters, amines, or sulfides. These are all multistep processes, since one usually takes [11C]carbon dioxide from the cyclotron, reduces it to [11C]methane, and then converts that to [11C]methyl iodide. (The square brackets stand for “no-carrier-added”, which means we do not add any nonradioactive CO2 to the process, though there is always some present anyway.) Our group tries to develop chemical methodologies to use [11C]CO2 directly from the cyclotron for labeling, without resorting to strong organometallic bases such as Grignard reagents or alkyllithiums. These methods avoid inefficient chemical transformations of our radioactive reagents and also allow us to label a wider range of functional groups, particularly carbonyls. You can see a review we published on this last year at the link below.

Our most recent contribution in this field uses a copper-mediated reaction for C-11C bond formation starting from [11C]CO2 and an aryl boronic ester to produce aryl carboxylic acids. It is important to note some of the differences between radiochemistry and “cold” chemistry with CO2. While many metal-catalyzed CO2-fixation reactions have been developed, most of them are run at high pressure. With [11C]CO2, this is not very easily done, since when we “scale-up” we are still working with well under 1 nanomole of 11CO2. We also need to have efficient trapping of [11C]CO2 in solution so the choice of an appropriate base that is also compatible with the labeling reaction is essential. What’s more, since the entire process should be done quickly and we prefer automation to “hands-on” manipulations, our purification usually consists of semipreparative HPLC and solid-phase extraction. We need these to be efficient and to limit the total mass of stuff used in the reaction. A good radiolabeling reaction is only part of the battle and does not necessarily amount to a practical method that can be used for PET imaging.

The molecule we chose to label is an approved retinoid drug called bexarotene. About two years ago, bexarotene was shown to clear cerebral amyloid plaques in a mouse model of Alzheimer’s disease by activating APOE. This represents an intriguing mechanism to exploit towards therapies for dementia. Accordingly, some families suffering from dementia rushed to get the drug for off-label use, and a clinical trial is also planned. However, it has not been established that bexarotene can cross the human blood-brain barrier, and the highly lipophilic structure suggests that passive permeability would be unlikely. For our study, copper-mediated [11C]CO2-fixation allowed us to prepare [11C]bexarotene suitable for PET imaging to evaluate drug biodistribution. You can find more details in our paper at the link below.”


Leave a Reply

Fill in your details below or click an icon to log in: Logo

You are commenting using your account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s