Pfizer is ramping up the use of positron emission tomography, an imaging technique, to vet compounds in development.
Credit: PHOTO BY ROGER RILEY, PFIZER
It's kind of like 'Star Wars,' " says Stephen Williams, executive director of clinical technology at Pfizer, describing positron emission tomography (PET), an imaging technique used at Pfizer to cull information on target compounds going into development.
Williams describes how it works: A radio-labeled ligand is placed on a receptor, where positrons emitted from the ligand come in constant contact with electrons. This produces -ray photons that are monitored by researchers. If a drug candidate reaches the receptor, it displaces the ligand, reducing or eliminating the -ray photons. No change in photon generation means the candidate goes in the kill bin.
"Our job in imaging is to make sure the drugs that deserve to die die early and cheaply, and to use the same technology to add value to the drugs that should be successful," Williams says. "Without knowing that a compound is reaching a target organ or receptor, you can carry on for three years doing a big efficacy study, and it would be futile."
Technologies such as PET imaging, high-throughput screening (HTS), and combinatorial chemistry are facing a minor backlash: Some observers suggest that traditional discovery methods like natural products research should be reassessed in light of the failure of new technology to deliver fast returns on the genomics breakthroughs of the 1990s (C&EN, Oct. 13, 2003, page 77). But research directors at major drug companies insist that the new tools play an important role in generating early-stage drug candidates. Most claim they have already established a high-tech front line for their discovery regimes.
Investment has increased significantly in recent years. Pfizer, for example, has used PET imaging to some extent for 10 years, but the company is now ramping it up, according to Williams. When Pfizer acquired Pharmacia last year, its imaging department benefited from Pharmacia's partnership with Amersham Biosciences, a leading supplier of radiopharmaceutical materials used in the PET technique.
GlaxoSmithKline invested more than $200 million in HTS and associated automation over the past three years, opening a three-story facility last year in Harlow, England, according to Peter Goodfellow, head of discovery research. The firm also converted its research facility in Tres Cantos, Spain, from natural products research to HTS and is constructing a new HTS facility in Upper Providence, Pa. GSK says it will add HTS capabilities at its Stevenage, England, facility as well.
Goodfellow admits that fast screening of chemical compounds and collection of data alone will not advance drug discovery. Companies need to develop a means of selecting compounds, structuring scans, and dealing with the data, he says.
On the biology side, GSK has also invested heavily in genomics research in order to define targets more precisely. "We believe very strongly that genomics is an important tool for the future," Goodfellow says.
Research directors admit, however, that high-tech tools got off to a shaky start in drug discovery. "Wall Street hyped HTS, target identification, and combinatorial chemistry," says Jonathan Knowles, president of global research at Roche. "They are all useful tools, but none makes a significant change in the efficiency of drug discovery. The only way to do that is take all of them and integrate them into an organization that allows you to exploit them."
Knowles says a Roche glucose kinase activator for diabetes in Phase I clinical trials is a rare example of the human genetics of a disease actually leading to a medicine in development. He insists, however, that genomics and its support technologies are finding their level. "It is not pie in the sky," he says. "It's already making an impact on how we discover drugs."