Nuclear imaging drug development tools

Drug discovery and development is recognised as a long, costly and risky process. The pharma industry is currently facing serious pipeline challenges characterised by rising R&D costs and declining productivity in new product approvals. It now takes almost $1 billion (€725 million) to bring a new drug to market and unless the efficiency and effectiveness of the drug development process are improved, it is estimated that by 2010, the cost to successfully develop a new drug could approach $2 billion (€1.450 billion). Much of this expense is the result of costly late stage failures.

Pre-clinical imaging of animals, also called pre-clinical molecular imaging, is considered as one of the more important tools in helping to prevent failures at the human clinical trial stage. More specifically, functional molecular imaging allows researchers to distinguish between a drug that fails and a study that fails to test the drug properly. Among the various functional imaging modalities used in both pre-clinical research and human clinical trials, the nuclear imaging modalities SPECT and PET are the most advanced and widely used. They are the only technologies that support the bench-to-bedside model. In many respects, both technologies are complimentary. The selection of either one requires careful consideration of the animal model and the characteristics of the drug under development.

Superior resolution
The most popular animal model of human disease is the mouse. SPECT is recommended over PET for imaging mice because of its superior resolution and quantification capabilities. The spatial resolution of systems such as Bioscan’s NanoSPECT for imaging mice is below one millimetre, thus enabling to obtain images with the same visual acuity as can be obtained from scanning humans. This is not the case for PET. Its resolution for imaging mice is greater than one millimetre and in addition, resolution is non-uniform across the field-of-view (FOV). Also, and unlike for SPECT, the sensitivity within the FOV is non-uniform for PET, thus making accurate quantification of biodistribution studies in mice or rats much more difficult with PET than with SPECT.

The second important consideration is the use of the radioisotope. Irrespective, it is desirable to engineer a true tracer, one that replicates the drug or biomarkers’s nature and behaviour. For drug candidates with slow kinetics, the best approach is to use SPECT tracers because of the longer half-live of the radioisotope. These drugs fall usually in the category of biopharmaceuticals; larger molecules for which the addition of a SPECT radioisotope does not impair the action of the drug or biomarker. For small molecules on the other hand, the PET isotope 11-C is the ideal radioisotope since it can be synthesised in the candidate drug. Unfortunately, the very short half-live and the low specific activity of the tracer restricts the use of this tracer to molecules that can be relatively quickly synthesized and for imaging studies of short duration. For other small molecule applications, radiohalogens for PET and SPECT may have to be used instead.

There are other considerations that play a role in selecting the most appropriate technology. A summary of all the factors that should be considered is presented in the following table.

0.3 - 0.4 percent; uniform
Higher specific activity: X10-X100

Sub-mm; almost uniform
10 x better volumetric resolution

Axial: 2cm-27cm (helical scan)

Whole-body: Yes; slow kinetics
Focused: Yes; both fast & slow

Whole-body: slow kinetics only
Focused: both fast and slow

Easier: uniform sensitivity and resolution; less PVE errors

Best for larger proteins, peptides, antibody fragments, hormones

Wide range of labels, incl. 125 I; fast and slow assays; dual-label

Lower energy à lower dose except for long-lived 125 I

Comparison table of pre-clinical PET and SPECT systems. For SPECT, this comparison applies only to multi-pinhole SPECT systems such as the NanoSPECT/CT.

BIO
Staf C. Van Cauter is Executive Vice-President of Bioscan Inc., Washington, DC, US. Prior to joining Bioscan, he was Corporate Vice-President and Chief Technology Officer of Packard BioScience Company until its acquisition by PerkinElmer, Inc. He served as a consultant to PerkinElmer from 2001 until 2003.