Avoiding the Pitfalls of Pre-Clinical Imaging

Pre-clinical or small-animal in-vivo imaging is in an exponential phase of growth in the research facilities of many academic facilities and pharmaceutical companies. This growth has been initiated by several factors, including the availability of technology purpose-built for the imaging of small animals, the high-visibility impact of imaging on the practice of human medicine, and the perception that research centers successfully employing imaging can reduce the time required to bring new promising therapeutic agents to the clinic.

Still, careful thought must be given in choosing the right imaging equipment as well as in planning how best to utilize imaging for the discovery of new therapies. There are some advantages that can only be realized by design and changing some well-established supporting technologies to realize the full potential of newly available pre-clinical imaging technologies.

Meeting the Clinical Translation Challenge:
Optical (luminescence and fluorescence) imaging, single photon emission computed tomography (SPECT) and positron emission tomography (PET) are used regularly in small animal research to study the molecular bases of disease non-invasively, and to guide the development of novel molecular-based treatments. Unlike optical imaging, SPECT and PET can probe subtle molecular signals deep within tissue, making these technologies suited for use in both small and large subjects. This ability to penetrate large subjects has lead to the establishment of SPECT and PET as clinical standards of care. Therefore, pre-clinical discoveries and developments using these nuclear imaging technologies rather than optical imaging are more likely to translate into the clinic.

Imaging a Mouse like a Man:
The use of SPECT and PET for biological research in small animals presents several challenges beyond those faced in clinical faculties. First, small-animal imaging must achieve sub-millimeter resolution so that images in mice as can be obtained with the same visual acuity as in humans. Second, a high level of detection sensitivity is needed to minimize the amount of radioactive probe that needs to be injected and to allow procedures to be completed within a 30-45 min period during which small animals can be anesthetized safely. To meet these challenges, one should consider using the recently introduced nano-SPECT and -PET imagers (Bioscan Inc, Washington, DC) which use multi-pinhole SPECT and high-density fine-crystal ring PET technology respectively.

Treating the mouse like a patient:
Another challenge in pre-clinical imaging relates to the necessity of immobilizing the animal during study. Such immobilization is accomplished using general anesthetics, which are well known to have significant effects on the cardiovascular, respiratory, and central nervous systems. Careful consideration should be given to the choice of anesthetic to study a particular process so that effects are minimized. The consistency of depth of anesthesia and the animal’s temperature during a study and from one study to another are also important. Such careful control of anesthesia and temperature is also necessary to ensure long-term survival of the animals in longitudinal studies, in which the same animal may be anesthetized and scanned weekly for 6, 8, or even 10 weeks. Fortunately, specially designed imaging chambers such as the Minerve system (Bioscan Inc, Washington, US) are now available to provide a comfortable imaging environment for the animal.

The Role of Disease Models in Understanding and Treating Disease:
Perhaps the best example of the incongruence between the potential of molecular imaging and the current pre-clinical imaging practice is found in oncology research. Clinical oncology has been profoundly changed by imaging technology because it made possible the non-invasive visualization of hidden cancer lesions in-situ, thus enabling to assay the extent of disease or the response to treatment. Pre-clinical imaging, by contrast, deals mostly with oncology models in which the cancer has been moved entirely out of internal organs, to a location which is directly and easily observable with traditional micro-SPECT or micro-PET imaging technologies. Without a doubt, this subcutaneous flank xenograft model has proved valuable, but it also has definite and well-documented shortcomings that can only be overcome by studying additional, complementary models with higher resolution nuclear imagers such as the recently introduced nano-SPECT/CT and nano-PET/CT scanners.

The advent of purpose-built nano-SPECT and nano-PET imagers enables to study advanced cancer disease models with tumors in internal organs rather than subcutaneous flank xenograft models. Such a model is illustrated above showing fused SPECT and CT images of spontaneous lung tumors in mice (courtesy Netherlands Cancer Center, Amsterdam, the Netherlands).

Staf C. Van Cauter, EVP, Bioscan Incorporated, Washington, DC
Prior to joining Bioscan, Mr. Van Cauter was Corporate VP and CTO of Packard BioScience Company until its acquisition by PerkinElmer, Inc. He served as a strategic consultant to PerkinElmer from 2001 until 2003. He holds an MSc degree in Industrial Engineering from the Higher Institute for Technology in Mechelen, Belgium and completed Postgraduate studies in Business Administration at the University of London.