Biomedical Engineering Reference
In-Depth Information
DDD process
Imaging
Input
Task
Deliverable
Output of phases
• Presence of drug target
Target
selection
Target validation
• Altered expression in
pathological condition
Drug target
D1: assay
development
HT assay
Compound
libraries
D2: HT
screening
Lead compounds
• Disease phenotyping
Biological
models
Drug eicacy in
disease models
D3: lead
optimization
• Quantitative assessment
of treatment eicacy
Annotated lead
compounds
• Quantitative assessment
of treatment eicacy
Drug eicacy and
safety in disease
models
Safety
assays
• Safety assessment
D4: proiling
• Biodistribution and PK
• Identiication of biomarker
Drug candidate
• Selection/stratiication of
patient population
POC of drug
mechanism and
clinical eicacy
POC
indication
Early clinical
development
• Quantiative assesment of
therapeutic eicacy using
biomarker
POC in man
Development
indication
Full clinical
development:
Phases I, II, III
Drug
FIGURE 7.1
Role of imaging in the DDD process. Conventional and molecular imaging approaches provide
information for validation of the drug target, for the evaluation of treatment efi cacy in models of human
disease during lead optimization and proi ling. A critical aspect in view of future clinical development is the
identii cation and characterization of biomarkers with prognostic value for clinical outcome. These biomarkers
are used in clinical proof-of-concept studies.
Abbreviations used
: drug discovery and development (DDD), high
throughput (HT), pharmacokinetics (PK), proof-of-concept (POC). The different gray levels of the individual
phases in the DDD chain indicate the translation from preclinical to clinical phases.
been obtained by using positron emission tomography (PET). Today, progress in imaging tech-
nologies has greatly enhanced the scope of imaging in DDD: so-called molecular imaging meth-
ods enable annotation of tissue structure with cellular and molecular information in animals and
in humans. These methods are based on the design of target-specii c exogenous imaging agents,
which selectively target the process of interest or on assays originally developed for imaging of
cells and cell networks, frequently involving genetic engineering to produce detectable imaging
signals (reporter gene assays).
7.2 MULTIMODAL IMAGING TECHNIQUES FOR DDD
In the subsequent sections we will discuss the role of conventional and molecular imaging in the
context of DDD. Before digging into imaging applications we will briel y discuss three important
modalities, magnetic resonance imaging (MRI), l uorescence imaging, and PET. Figure 7.2 sche-
matically describes the source of signals, the physical principle leading to image generation, the
inl uence of the (biological) environment on the signals detected, the principle of spatial encoding,
and the spatial resolution provided for the respective modality.
