by Caitlin Smith
Conversations have arisen between the data-rich phenomenon of molecular imaging and the behemoth process of drug discovery. The result is good news for everyone: the former could expedite the latter considerably, bringing better, less expensive drugs to market – faster. New technologies are encouraging this dialogue to continue fruitfully.
Shahram Hejazi, president of Carestream Molecular Imaging, notes that the promise of molecular imaging for drug discovery is compelling. “It can cost up to $1 billion to bring a new drug to market,” says Hejazi. “Optical molecular imaging could potentially cut that process in half while speeding the introduction of a promising new therapy. Therefore, there is a huge incentive for all participants in the drug development cycle—including academic researchers, molecular imaging companies, drug firms and the FDA—to work together to help validate the safety and efficacy of optical imaging for drug development and ultimately, for clinical use.”
in vivo and whole-animal imaging
When it comes to drug discovery, it sometimes pays to move quickly to an in vivo system. “Theoretical and in vitro tests do not always prove to be reliable indicators of what works in vivo,” says David Stout, director of the Preclinical Molecular Imaging Center at the UCLA Crump Institute for Molecular Imaging. “Much time and effort can be spared by a couple images in mice.” Advances in molecular imaging are being fueled by research in academia and industry alike. Stout, who oversees more than 10,000 experiments per year and assists over 40 principal investigators with their research, sees researchers moving their experiments to the clinic faster. “We are doing more PET probe development specifically geared towards quick translation to the clinic,” says Stout. “We are now able to make, evaluate and test in rodents, then humans, in less than 8 months, compared to historical processes requiring many years of effort.”
Another tool speeding in vivo research is multiplexing – measuring multiple fluorescent signals simultaneously. Carestream Molecular Imaging recently introduced their new Kodak In-Vivo Multispectral Imaging System FX, which can separate multiple fluorescent signals in small animal imaging. According to Hejazi, the system “can be programmed to automatically capture a series of images at different excitation wavelengths, which are then analyzed with sophisticated software to unmix signals and better identify the region of interest. In addition, x-ray and white light images can be captured and spatially co-registered with the image for improved localization of biomarkers.”
Previous issues in whole-animal imaging are also less problematic today. Normal body movements – the heart beating, lungs moving with breathing, arteries pulsating with blood flow – typically cause some blurring of images. The blurring can cause problems for locating biomarkers, but new techniques are overcoming this obstacle. According to Jean-Luc Vanderheyden, global molecular imaging leader at GE Healthcare, their “Motion Free technology is enhancing PET/CT and SPECT imaging through its ability to quantify and model the natural action of organs, and to build that information into an imaging study, compensating for the effects of the movement on image acquisition, to produce clearer, crisper views of a target tissue or lesion.”
High-content imaging
The conversation between molecular imaging and drug discovery wouldn’t be complete without the high-throughput methods and high-content screening (HCS) so vital to the processes of target identification, target validation, or drug candidate selection. “The most exciting area in image-based drug discovery today must be high-content imaging/screening,” says Magnus Persmark, senior product manager for Invitrogen's Molecular Probes. “Simply put, it is high-throughput microscopy and analysis of images of cellular morphology and signaling events, often involving fluorescent labels.” Many of Molecular Probes’ new products were developed to aid drug discovery research, particularly in HCS. For example, their HCS LipidTOX™ assay characterizes phospholipidosis, a toxic side effect on lipid metabolism triggered by certain drugs. In addition, their FluxOR™ Thallium Detection Kit is a fluorescence-based assay for high-throughput screening measurements of potassium ion channel and transporter activities.
“With the resolution and content richness inherent in image-based methodology,” says Persmark, “HCS provides a very powerful tool to examine multiple cellular targets and parameters in a large number of individually imaged cells and [to] quantitatively assess the data.” Looking forward, Persmark sees the development of more complex methods to analyze data generated by HCS, “iteratively enabling more refined assays and queries, thereby increasing our understanding of both drug structure-activity relationships and how phenotypic responses correlate with biological effects of drugs.”
Imaging biomarkers
Imaging biomarkers – whether peptides, proteins, or cells – are specific indicators of changes in biological processes. For example, GE Healthcare is developing biomarkers to target amyloid plaques, specific cell-surface receptors, and indicators of metabolic pathways. According to Vanderheyden, imaging biomarkers “represent a critical link in the translation of knowledge about disease mechanisms, drug targets, and therapeutic strategies from the lab bench to preclinical animal testing, to clinical drug development and the diagnosis and treatment of disease.” He notes that in drug development, validated imaging biomarkers can shorten developmental timelines, reduce late-stage attrition of drug candidates, and allow for easier transitions from one stage of drug development to the next.
Important though biomarkers are, Hejazi notes that they can also be obstacles for some scientists. In order to identify and characterize biomarkers in the development of disease models, researchers need the ability to label and measure the biomarkers. “This is where molecular targeting chemistry such as the functionalization of an imaging agent is utilized,” says Hejazi. “However, such bioconjugation chemistry is not trivial, and can pose a barrier for medical researchers who may lack a chemistry background or access to the required chemistry resources.”
Put your data where your markers are
A challenge facing molecular imaging and drug discovery is making the connection between pre-clinical molecular imaging data and clinical imaging. “For doing this, there are 3 necessary criteria,” says Kirtland Poss, president and CEO of VisEn Medical. “Validated target biomarkers of disease, biocompatible fluorescence agents that read validated disease biology in vivo, and quantified data in pre-clinical imaging such that the data on the in vivo biomarker itself can be linked both back into the profiling data, and forward into the clinical data.” Linking validated disease biomarkers with quantitative data on those biomarkers in vivo is in progress. “This comes from a combination of novel biocompatible fluorescence imaging agents (like VisEn’s ProSense, AngioSense, and OsteoSense), and quantitative tomographic imaging data generated with [our] FMT technology,” says Poss. VisEn Medical’s ProSense imaging agent, which measures changes in protease activity, will be used in clinical imaging next year.
The back-and-forth between drug structure and phenotypic response is central to the drug development process, which makes molecular imaging a well-suited partner. “Instead of waiting months to see if a prospective drug has shrunk a tumor, researchers can assess either positive or negative results within cancer cells within weeks, days or even hours,” Hejazi says. “Therefore the time it takes to develop a drug could be cut by more than half—creating a dramatic improvement in the rate at which new drugs can be brought into clinical use.” Vanderheyden agrees: “The goal is to introduce imaging early in the drug development process, so that it can be useful in the transition of the development process into humans.”
