In Vivo Imaging in the Preclinical Evaluation of Disease Progression, Treatment Efficacy, and Safety

DISCOVERY SERVICES TECHNICAL BULLETIN In Vivo Imaging in the Preclinical Evaluation of Disease Progression, Treatment Efficacy, and Safety Technical ...
Author: Annabella Kelly
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DISCOVERY SERVICES TECHNICAL BULLETIN

In Vivo Imaging in the Preclinical Evaluation of Disease Progression, Treatment Efficacy, and Safety Technical Focus: CT, MRI, MRS, PET/SPECT, & DEXA

Introduction

in a variety of 2D planar images. Because CT uses X-rays, there are some limitations in the clinic due to radiation exposure limits. Compared to other imaging technologies (see below), CT also has more limited molecular imaging applications due to its relatively poor sensitivity to molecular probes. However, CT is ideal for anatomic imaging of bone, lung, kidney, and tumors of the head, lung and abdomen.

The use of preclinical imaging is increasing as the power of these tools has been demonstrated through a variety of animal models that enable early drug screening and decision making. Anatomical, molecular, and functional imaging can provide valuable information to help understand the activity of compounds in development, supporting studies evaluating compound activity (mechanism of action, efficacy) as well as safety and toxicity. Combined with advances in analytical tools and the use of systems that are able to image not only small animals but larger species such as dogs and nonhuman primates, imaging is increasingly used in large molecule (antibodies, proteins) evaluation and to investigate abnormal findings in late stage toxicity studies.

In preclinical studies, CT has been used extensively to monitor changes in bone that occur in models of osteoporosis, fracture repair, osteoarthritis and rheumatoid arthritis, and metastatic tumor-induced bone erosion. An example of the use of CT in a bone healing model is shown in Figure 1.

This Technical Bulletin focuses on the preclinical use of imaging tools that are critical in diagnostic clinical settings and considered translational biomarkers in the clinic, specifically DEXA, CT, MRI, MRS, and PET/SPECT. Each of these modalities will be briefly reviewed, followed by case examples that demonstrate the types of drug development questions that can be answered using these modalities.

Figure 1. Model of bone healing/fracture repair in osteoporosis in rats. Model shows a time and dose-responsive enhancement of bone healing.

Computed Tomography (CT) CT is a widely used, clinically translatable modality that also has wide use preclinically. CT uses a large series of two dimensional x-rays taken around a single axis of rotation to generate a three dimensional image. Data can be reconstructed in 3D or analyzed Page 1

be evaluated with the use of contrast agents using Perfusion or Dynamic Contrast Enhanced CT (DCE-CT). After the injection of the contrast agent, the change in signal intensity over time in a region of interest can be mathematically modeled to estimate parameters related to blood flow and permeability. This technique has been used both preclinically and clinically to measure vascular integrity in organs such as the brain, kidney, liver, and lungs, as well as for monitoring changes in tumor vascularity and perfusion during disease development and treatment. The primary advantages are speed and simplicity. A multi-slice CT scanner can acquire a three-dimensional image in less than 1 second with high spatial resolution (

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