Biomedical Engineering Reference
In-Depth Information
7
Imaging in Drug Discovery
and Development
Markus Rudin and Thomas Mueggler
CONTENTS
7.1 Imaging in Drug Discovery and Development ................................................................... 107
7.2 Multimodal Imaging Techniques for DDD......................................................................... 108
7.2.1 Conventional Imaging............................................................................................ 109
7.2.2 Molecular Imaging Approaches ............................................................................ 110
7.2.2.1 Target-Specii c Imaging Assays............................................................. 110
7.2.2.2 Molecular Imaging Strategies, Imaging Targets.................................... 111
7.3 Selected Imaging Applications in DDD.............................................................................. 113
7.3.1 D1: Target Validation ............................................................................................. 113
7.3.2 D3/D4: Lead Optimization and Drug Proi ling..................................................... 114
7.3.3 Translational Studies, Biomarker........................................................................... 117
7.4 Does Imaging Add Value to the Drug Discovery Process.................................................. 119
7.5 Imaging in DDD: Challenges.............................................................................................. 120
7.6 Conclusions ......................................................................................................................... 121
Further Readings ............................................................................................................................ 122
7.1 IMAGING IN DRUG DISCOVERY AND DEVELOPMENT
The genomics/proteomics revolution has led to an explosion in the number of potential targets for
therapeutic interventions to something in the order of 5000-10,000. This requires extensive change
in strategies for drug discovery and development (DDD) involving high-throughput approaches for
target validation and compound screening. The individual phases in the modern DDD process com-
prise the selection of a potential drug target (D0), which may be based on clinical observations,
genetic linkage maps, or on a mechanistic hypothesis (Figure 7.1). The next two phases are related
to high-throughput screening of large compound collections and comprise the development of the
screening assay (D1) and the high-throughput screening procedure itself (D2), hopefully leading to
chemical lead compounds, which are optimized by chemical derivatization during lead optimiza-
tion (D3). Compounds are compared with regard to efi cacy and potency in relevant animal models
of human disease to identify an optimized drug candidate(s) for further characterization including
extensive safety assessment (D4). Thereafter, the drug candidate enters the clinical development
phases (Phases I-III).
Noninvasive imaging techniques have been used in the DDD process for decades, provid-
ing structural, physiological and metabolic information in a temporospatially resolved manner
throughout the various phases, in particular during phase D3 and for early clinical studies (Figure
7.1). In animals, cellular and molecular information has, in general, been obtained invasively; for
example, the biodistribution of drug molecules has been assessed by mapping the distribution of
a radiolabeled analog using autoradiographic methods. In clinical studies, similar information has
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