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

Animal Imaging Transforms Development

Widespread Use of Noninvasive Technology in Models Has Accelerated Drug Research

  • Click Image To Enlarge +
    The image shows 18F-NaF PET signal at sites of bone disease/osteoporotic activity. (Charles River)

    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.”

  • Bridging the Mouse-Man Gap

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

    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.”

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