November 1, 2009 (Vol. 29, No. 19)

Widespread Use of Noninvasive Technology in Models Has Accelerated Drug Research

Rapidly evolving imaging technologies were front and center at the “World Molecular Imaging Congress”, which was held recently in Montreal. This year’s meeting provided a timely forum to discuss the use of imaging in drug development, an application that is experiencing vigorous growth.

“Traditional tracking of disease was invasive. Imaging allows it to be less invasive,” reported Patrick McConville, director of imaging at Charles River. Dr. McConville explained that obtaining the higher resolution necessary in animal models has been challenging.

“The most prevalent models of human disease are in mice,” he said. “Imaging in small animals has involved advancements that have led to dedicated small-animal imaging technologies that parallel clinical equivalents. Imaging can be a costly endeavor, but it can be used to generate multiple disease endpoints in the same animals, including molecular-level information, and has accelerated disease and drug research.

“Imaging modalities—CT, ultrasound, PET, MRI, and SPECT—have seen wide application in clinical diagnosis and are now emerging as a force in drug development,” said Dr. McConville. “These modalities complement each other and can be combined strategically. The field has matured to leverage the unique capabilities of multiple modalities.”

The image shows 18F-NaF PET signal at sites of bone disease/osteoporotic activity. (Charles River)

Bridging the Mouse-Man Gap

At the meeting, Bruker BioSpin showcased helium-cooled probes that enable microscopic MRI in neuroimaging and self-gated cardiac MRI techniques to automatically trigger and acquire the moving heart of rats and mice at high temporal resolution.

“A mouse heart is only about 7 mm, so the little problem is a big one,” said Thorsten Thiel, Ph.D., director of marketing communications. “If volumes shrink by 1,000, the smaller the object, the less signal intensity available for accurate and detailed image acquisition.” The challenges inherent in establishing MRI technology in the microworld include quality concerns, the wide range of small-animal applications, short experiment times, demand for simple workflows, and high-throughput requirements, according to Dr. Thiel.

ClinScan, produced in cooperation with Siemens, allows a direct and fast transfer of preclinical studies on animal models to clinical studies on humans, Dr. Thiel reported. It includes syngo, a clinical-user interface that orients workflow, parallel working, and parallel scanning. “The software is simple to use, and the front end user sees no difference when compared to human MRI interfaces,” he added.

It also features low temperature, closed cycle cooled RF-coils, and preamplifiers that reportedly deliver an increase in sensitivity of a factor of 2.5 over standard room temperature RF-coils in routine MRI applications.

“Our latest cardiac imaging product is IntraGate, a technique that allows users to acquire high-temporal and high-spatial resolution images without external triggering devices. IntraGate enables a retrospective construction of cine movies at a high resolution of less than 100 microns. The ease of use of this approach enabling small-animal cardiac imaging is unique and opens preclinical MRI to a broader audience due to less training and experience required,” he concluded.

Bioscan presented results from its NanoPet/CT dual-modality preclinical imager at the congress. “With our sub-mm resolution system, you can use PET to study the absorption, distribution, metabolism, and excretion characteristics of candidate molecules with fast assay kinetics in a large variety of animals,” explained Staf C. Van Cauter, Ph.D., executive vp.

The NanoPET/CT’s PET detector comprises 12 high-definition detector arrays of 85 x 39 LYSO crystals of 1.12 x 1.12 x 13 mm3 at a packing fraction of 92%. Data acquisition and processing architecture includes 12-bit high-speed digital to analog converters with 130 MHz sampling. The optional CT system uses helical scanning with volumetric cone-beam technology and a microfocus source with variable magnification, enabling image clarity and detail while minimizing radiation dose to the subject, Dr. Cauter added.

“Both the PET and CT systems share the same axis of rotation and scan origin to enable real-time, accurate image fusion, with no quantitation errors due to partial volume effects or image artifacts caused by nonuniform field-of-view sampling. Our system has been designed as a translational medicine tool,” said Dr. Van Cauter. “You get the same image acuity in animals as small as mice as you would in a human scanner.”

Optical imaging has an advantage over traditional research methods, particularly with regard to cost, according to Stephen Oldfield, director of imaging at Caliper Life Sciences. “It is high throughput and low cost, only a couple of dollars per animal,” he added. “The industry is growing. Looking at the rate of publications, the numbers have grown exponentially. Everything is driven by animal models and new chemistry.” 

Scientists at Caliper showcased the IVIS Lumina XR at the meeting. It is reportedly capable of imaging all common fluorescent and bioluminescent reporters or dyes. The system is equipped with up to 21 filter sets to image reporters that emit from green to near-infrared. “You can look at five animals at a time, quickly, so it’s possible to do an efficacy study at the rate of a compound a week,” noted Dr. Oldfield.

In a case study on ultimate quantitation and x-ray coregistration, it was demonstrated that using a tomographic technique colocated with MRI provided the best quantitation. “It told us how many picoliters of live cells are in a tumor using bioluminescence and fluorescence, which can help researchers determine the active and passive cells. What we saw most of was tumor recurrence and infectious disease reservoirs, we thought the animal was cured, but we found reservoirs in bone marrow. I can’t imagine any other technique that could make this possible.”

Near-IR fluorescent agent targeted to LPS-induced inflammation in mouse lung. (Carestream Molecular Imaging/K. Dhaliwal, University of Edinburgh)

Clinical Translation

GE Healthcare has a strong stake in molecular imaging, but Jean-Luc Vanderheyden, Ph.D., global molecular imaging leader, technology and medical office, noted that molecular imaging means different things to different people. “We got our start in molecular imaging as applied to drug development, but imaging is a rapidly expanding and inclusive field.”

At the congress, the company presented a full range of solid-state imaging technologies—the ability to see the entire animal—“which may well become the standard for small-animal study,” said Dr. Vanderheyden.

GE’s eXplore speCZT is a full-ring solid-state detector small-animal SPECT that focuses on high throughput and rapid dynamic imaging. It uses a cadmium zinc telluride (CZT) detector, allowing for full 360º coverage around the animal and high-energy resolution to enable dual or triple radio-nuclide imaging. The increased sensitivity of speCZT helps medical researchers perform dynamic small-animal SPECT imaging to precisely quantify radio-tracer uptake and identify morphological changes, Dr. Vanderheyden said.

“The technology from this small-animal SPECT was used to help create advances in nuclear cardiology patients,” he added. “Imaging has been part of preclinical studies for decades, but the movement toward noninvasive imagery is quite new. The convergence of technologies, provide researchers the materials and knowledge they need to do their jobs.”

This mouse image from the GE eXplore specCZT CT120 shows a whole-body, dynamic SPECT image overlaid on a CT scan. (Dr. P. Choquet and Pr. A. Constantinesco, Hopital de Hautepierre)

Near Infrared

LI-COR Biosciences’ Pearl Imaging System is optimized for use with LI-COR IRDye® Infrared Dyes for NIR imaging at 700 and 800 nm, according to Jeff Harford, senior product manager.  “There is a great interest in real-time imaging, and the new Pearl® Impulse collects images at a fast frame rate, and the sensitivity allows tumors to be detected in the animals before they are even palpable.” The New Pearl Imager Impulse will be ready to ship in early 2010, Harford noted.

Working in near infrared has unique advantages. “Working in visible wavelengths interferes with fluorescence detection due to high background signal from surrounding tissue, and white light (in contrast to the Pearls’ laser excitation) does not penetrate tissue very effectively,” Harford added. “Near infrared is the window through which a broad spectrum of in vivo applications are possible.”

“Many people have been working with green fluorescent proteins, visible reporters that are transfected into cells. They are difficult to see because of the auto fluorescence of tissue. But now, there is a new fluorescent protein for near-infrared imaging that offers some tremendous opportunities for small-animal work.”

PET and CT Imaging

“Siemens Medical Solutions makes small-animal PET, SPECT, and CT imaging scanners,” said Anne M. Smith, Ph.D., director of preclinical collaborations, Siemens Healthcare Molecular Imaging. “For PET, we have the Inveon small bore system with a 12 cm opening and a larger microPET 22 cm bore system that can be used for primates and multirodent studies. The 22 cm bore is the only primate-sized system on the small animal PET imaging market.”

Two challenges that vendors encounter in the PET small animal arena are sensitivity and resolution. “Creating greater sensitivity allows the use of less radioactive dose or the same dose which gives more signal,” explained Dr. Smith. “We’ve increased the sensitivity from less than 4% to greater than 9.5%, and improved the resolution from greater than 2 mm to less than 1.6 mm in approximately a seven-year period.”

Dr. Smith’s group, part of the molecular imaging division at Siemens, also manufactures clinical molecular imaging systems, cyclotrons, and radiochemistry equipment. In addition, the division distributes radioisotopes via PETNET operations. “Our portfolio ranges from radioisotope delivery and biomarker discovery to small-animal imaging and clinical imaging solutions,” said Dr. Smith.

In the CT realm, Siemens’ systems “give  users the resolution needed to do ex vivo studies and the field of view required for in vivo studies,” she reported. “Customers demand more multimodality imaging; our Trimodal option provides PET, SPECT, and CT on the same gantry. Users also require more streamlined workflow, which not only includes the acquisition software but also the analysis software.

“We offer the Inveon Research Workplace (IRW) to fill this need. We plan to expand IRW’s multimodality imaging capabilities to include other modalities, such as optical, MRI, and ultrasound.” Dr. Smith noted that chemistry and molecular biology to develop new PET biomarkers as well as biomarkers in other modalities as being key to continued growth in the field.

Sofie Biosciences launched its GENISYS™ PET imaging system at the meeting. Turnkey installation and user-friendly operation means GENISYS is suitable for large and small labs, according to the company. Integration of physiological control with measurement output provides researchers with reproducible, quantitative information without the use of traditional, expensive hardware architectures. 

“PET should be less complicated and available to anyone who wants to incorporate it into their research routine,” said Patrick Phelps, president and CEO. “Sofie worked closely with the UCLA Crump Institute to develop a next-generation PET system that provides people with impressive images and the output they desire, all within an imaging device that manages the health of your animal.”

Multimodal Imaging

Carestream Molecular Imaging demonstrated its multimodal technology at the conference. “It allows multispectral fluorescence, luminescence, and radioisotope imaging combined with x-ray imaging without ever moving the animal,” said Bill McLaughlin, director of advanced research and development.

“This makes it possible to precisely coregister the anatomical location of molecular signals from optical and nuclear imaging. Others attempt this, but we can do it precisely because all of these different image modalities are taken in the same system and at the same focal plane.”

McLaughlin noted that the nature of Carestream’s product’s design is a key factor in meeting some of the greatest challenges in the field. “One thing we did was calibrate the light source in such a way that the field is flattened to correct for any uneven lighting on the animals. With our system, it doesn’t matter where you put the animal on the surface, you will get consistent, repeatable results.”

Carestream systems also allow imaging from underneath the animal so it can be placed in its natural position—on its belly—for most of the imaging that is done on tumors and other disease states. “Gravity helps us out by spreading the animal more evenly on our imaging surface, which serves as the focal plan for all the different modalities,” added McLaughlin. “One thing that is important from an image and measurement standpoint is positioning the animal in a consistent way.

“Researchers need repeatable, measurable results in a high-throughput setup. We try to take as much variability out of animal imaging as we can so that researchers not only get great images, but also get reliable data.” 

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