NOVEMBER 2003

MI comes to the rescue of pharmaceutical companies

Strategies promise to accelerate the pace of drug research and development

By: Paula Gould

Drugmakers are looking to molecular imaging as the biotechnical equivalent of aspirin to treat their biggest headache. Genomic research has identified countless more molecular targets associated with disease than novel drug treatments could ever address, and advanced combinatorial chemistry techniques are producing millions of complex molecular compounds with unknown functional properties that beg for testing. Finding a new molecule A to home in on target B and modify the progression of disease C safely and efficaciously aptly sums up the entire drug discovery and development process.

Molecular imaging has the potential to rapidly sort the promising from the not-so-promising compounds and measure the response of disease to experimental therapies quickly, according to speakers at the Society of Noninvasive Imaging in Drug Discovery meeting, held in conjunction with the Academy of Molecular Imaging international conference in September.

"What we really need is a selection of tools that help us better manage the business risks involved in launching a new platform," said Dr. David Mozley, senior research scientist at Eli Lilly.

To get the most from these imaging tools, Eli Lilly is operating a virtual imaging center:

All imaging R&D is outsourced to academic research sites. In contrast, both Merck and GlaxoSmithKline (GSK) are strengthening in-house facilities for preclinical imaging.

All three companies assume that future drug testing will require a multimodality approach. Researchers at GSK's aptly named Molecular Imaging Center of Excellence (MICE) will ultimately be able to perform high-field MR, microPET, microCT, and optical imaging. Merck's new imaging center, under construction in West Point, PA, will be similarly equipped with PET, microPET, microCT, micro-ultrasound, and high-field MR/MR spectroscopy capabilities.

Looking at specific modalities, optical imaging methods can be combined with small-animal PET programs to hasten investigation of novel drugs, said Dr. Sanjiv Sam Gambhir, director of molecular imaging research at Stanford Medical Center. Absorption and scattering effects of light through tissue make optical imaging highly problematic in humans, but these effects are greatly reduced in rodents because the light has far less distance to travel.

Two options exist for imaging with light. In bioluminescent imaging, a CCD camera detects light generated within an animal containing luciferase genes that have reacted with an injected chemical substrate. If the luciferase genes are tailored to switch on only when another gene is activated, emitted light can be used to monitor biomolecular processes. An alternative involves tagging genes with a fluorescent marker that absorbs and remits light at a different wavelength. If the tagged gene has been reengineered to serve as a smart probe-meaning it activates only when it reaches a certain site-induced fluorescence can be used to assess drug treatment models, Gambhir said.

Mozley would like to see nuclear imaging investigators pursue SPECT programs alongside their PET work. Measurement of target occupancy levels with PET, using radiolabeled drugs, is well established. SPECT could theoretically be used in a similar manner, providing the technique generated similarly quantitative data, he said.

SPECT has several advantages over PET, due to the comparably longer half-lifes of gamma-emitting radioisotopes, Mozley said. Investigators could acquire multiple fields-of-view from the same subject. Radiopharmaceuticals manufactured at a single site could be transported to multiple locations for parallel studies. Longer lasting radioactive nuclides are also more suitable for substitution into larger, slower acting pharmaceuticals.

"Our drugs are becoming bigger, greasier, and they're moving more and more slowly," Mozley said. "I would encourage the many outstanding investigators who are focused exclusively on PET to consider including single-photon emitters in their portfolio. They may have an important role to play in medicines that are actually meaningful."

PET can also be paired with MR in the development of drugs to treat central nervous system disorders, said Dr. Richard Hargreaves, executive director of pharmacology and imaging at Merck. While PET has an important role in neuroreceptor mapping and target occupancy studies, the functional, structural, and metabolic data from MR and MRS can reveal complementary information on CNS drug activity. MR can additionally help researchers study the progress of neurodegenerative disorders such as Alzheimer's disease by identifying potential biomarkers for assessing the efficacy of novel disease-modifying drugs.

"Looking to the future, we want to move the science of MRI beyond neurophysiology or 'neophrenology,'" he said. "By selectively combining the highly specific drugs we are making with functional MRI paradigms, we hope to learn more about the chemical neurotransmitter anatomy of brain functions, such as cognition, and whether we can fix deficiencies with drug therapy."