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 comprise 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 optimization (D3). Compounds are compared with regard to efficacy 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, providing 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


Output of phases

Drug target

HT assay



Lead compounds ™



Annotated lead compounds

POC indication

Development , indication

Drug candidate

POC in man

DDD process

Target selection

D1: assay development

D2: HT screening

D3: lead optimization

D4: profiling


D4: profiling

Drug candidate

POC in man

Full clinical development: Phases I, II, I


Target validation

Drug efficacy in disease models

Drug efficacy and safety in disease models

POC of drug mechanism and clinical efficacy


Presence of drug target Altered expression in pathological condition

Disease phenotyping Quantitative assessment of treatment efficacy

Quantitative assessment of treatment efficacy Safety assessment Biodistribution and PK Identification of biomarker Selection/stratification of patient population Quantiative assesment of therapeutic efficacy using biomarker


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 efficacy in models of human disease during lead optimization and profiling. A critical aspect in view of future clinical development is the identification 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 technologies has greatly enhanced the scope of imaging in DDD: so-called molecular imaging methods enable annotation of tissue structure with cellular and molecular information in animals and in humans. These methods are based on the design of target-specific 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).

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