Chemical Process Advance May Simplify Drug Development

A new chemical process developed by a team of researchers greatly increases the utility of positron emission tomography (PET) in creating real-time three-dimensional (3D) images of chemical process occurring inside the human body.

This new study, conducted by Dr. Tobias Ritter, associate professor of chemistry and chemical biology at Harvard University (Cambridge, MA, USA), and colleagues holds out the enticing possibility of using PET scans to peer into any number of functions inside the bodies of living patients by simplifying the process of creating “tracer” molecules used to create the 3D images.

Pharmaceutical companies are developing new treatments by studying the way “microdoses” of drugs behave in the bodies of living humans. Researchers using noninvasive tests to assess the efficacy of drugs aimed at fighting disorders such as Alzheimer’s disease, and identify the physiologic differences in the brains of patients suffering from schizophrenia and bipolar disorder.

As described in the journal Science on November 4, 2011, the process is a never-before-achieved way of chemically converting fluoride into an intermediate reagent, which can then be utilized to bind a fluorine isotope to organic molecules, creating the PET tracers. Frequently used in combination with computed tomography (CT) scans, PET imaging works by detecting radiation emitted by tracer atoms, which can be incorporated into compounds used in the body or attached to other molecules.

“It’s extremely exciting,” Dr. Ritter said, of the breakthrough. “A lot of people said we would never achieve this, but this allows us to now make tracers that would have been very challenging using conventional chemistry.”

The new process builds on Dr. Ritter’s earlier fluorination research, which reduced the risk of damage to the original molecules by reducing the amount of energy needed to create fluorinated compounds, and involved the development of a novel, “late-stage” process that allowed fluorination to take place at the end of a compound’s synthesis, eliminating worries about the extremely short, two-hour half-life of the fluorine isotope used as a tracer.

Dr. Ritter’s process starts with fluoride, which is chemically altered to create an intermediate molecule, called an electrophilic fluorination reagent. Equipped with the reagent, and using the late-stage fluorination process developed in Dr. Ritter’s lab, his team is then able to create fluorinated molecules for use in PET imaging.

The advance opens the way for pharmaceutical companies to use the comparatively simple, noninvasive scans to track how microdoses of drugs behave in living individuals, with the potential payoff coming in greatly more efficient and less expensive drug development. “One of the most immediate applications of this is in using molecular imaging to give us an understanding of the biodistribution of a drug,” Dr. Ritter said. “If a pharmaceutical company is developing a drug to treat schizophrenia, they could use this test to see if it enters the brain. If early tests show it doesn’t, they would be able to kill the project before spending a great deal of time and money on it.”

The technique could even be used to uncover the physical characteristics of disorders that until now have been limited to phenomenologic descriptions. Using biomarkers related to specific disorders, researchers could use fluorination to identify biologic differences between schizophrenia and bipolar disorder, and use that data to develop treatments for both. “I don’t know if we’re ever going to reach that point,” Dr. Ritter said. “But that’s what this project may be able to deliver in the long term. The way my group works--we want to solve big problems, and we’re willing to sacrifice to get there. This is one problem that is worth a little bit of sweat.”

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