Molecular imaging strategies for drug discovery and development
Introduction
Historically, in vivo imaging strategies largely relied on visualization of gross anatomy, and detection of diseased tissue was based on morphological alterations or abnormalities. Thus, the primary role of non-invasive imaging was to aid the clinician in diagnosing the presence, location and severity of a potential disease. Although the non-destructive nature of in vivo imaging enabled clinicians to monitor and follow responses to selected therapies, in general, imaging was focused at diagnostics and was not thought of as an inherent component of the drug discovery and development processes.
Within the past decade, a paradigm shift has occurred; imaging sciences are now adding a new dimension to our understanding of basic biological and pharmacological mechanisms. Researchers can now perform non-invasive longitudal studies of biological processes in intact cells and living organisms, pinpointing the spatio-temporal dynamics of specific molecular targets. This new set of molecular probes, detection technologies and imaging strategies, collectively termed molecular imaging, is providing researchers and clinicians alike, new opportunities to visualize gene expression, biochemical reactions, signal transduction, regulatory pathways and direct drug action in whole organisms in vivo [1•]. Collaborative efforts of physicists, molecular biologists, biochemists, chemists, computational biologists, computer scientists and clinicians have led to recent advances in instrumentation and detection devices, development of target-specific probes and genetically encoded reporters, and generation of disease-specific reporter animal models. As a consequence, molecular imaging has gradually evolved into an important tool in the process of drug discovery and development [2, 3, 4, 5]. Thus, from target identification by genomics, proteomics and bioinformatics, through compound screening and target validation to pre-clinical toxicological and clinical studies, an emerging central role for molecular imaging has become evident.
Novel molecular therapies and cures are gradually emerging from the refined map of the human genome, from proteomic screens and from our increasing understanding of the molecular basis of pathogenesis. In particular, in the case of cancer therapy, selective inhibitors are envisioned to gradually replace the more general chemotherapeutic poisons. Clinical, epidemiological and bioinformatical data suggest that population-wide genetic polymorphism may dictate the responsiveness to molecular therapy (i.e., pharmacogenomics [6]). Thus, novel drugs are envisioned to be specifically ‘tailored’ to selected patients or cohorts. This molecular complexity offers new targets for therapeutic intervention, but demands innovation in drug development, shifting back and forth through in silico (bioinformatics, structure–function analyses), in vitro (purified proteins, cell lysates), as well as in cellulo and in vivo studies rapidly and efficiently. Generation of reporters for targeted drug action, interchangeable between in vitro, in cellulo and in vivo screens and assays, has become an integral component of both rational and ‘screen-based’ drug design strategies, accelerating the drug development process and easing the transition from purified targets to cells, animals and humans.
In this short review, we focus on state-of-the-art molecular imaging strategies and paradigms and, by highlighting recent developments in this field, illustrate the emerging role of molecular imaging in the process of drug development.
Section snippets
Choosing an appropriate imaging modality
Different imaging technologies exploit interactions of various forms of energy with tissues to non-invasively visualize internal structures within the body. Many of these imaging technologies were initially developed to be used in humans, but have been scaled down in the past decade to allow high resolution imaging of small laboratory animals [7]. Computerized tomography (CT) and ultrasonic imaging (US) are still the main tools for providing highly resolved structure-oriented information, while
Injectable drugs
Although valuable functional information can be derived from intrinsic properties of tissues (e.g., T2*-weighted MRI, diffusion-weighted MRI, infrared thermal imaging or Doppler-assisted US), exogenous injectable probes and contrast enhancing agents provide advanced molecular and cellular analysis of physiological processes and drug action in vivo. The most direct approach to study the pharmacokinetics of a certain drug by means of imaging is to directly label the drug with a
Imaging genetically encoded reporters
Studies in rodent models demonstrate the feasibility of reporter gene imaging to visualize and quantitatively analyze central signaling pathways in vivo, such as transcription, translation, protein–protein interactions and post-translational protein modifications [1•]. This aptitude to genetically manipulate cells and animals to report on specific molecular events has a tremendous effect on our ability to analyze the effects of novel drugs on their direct as well as downstream targets in living
Conclusions
There have been many recent advances in the field of molecular imaging, and in particular in the utilization of such strategies for the discovery and development of novel therapeutics. Many aspects of drug development can be facilitated using molecular imaging as an integrative tool to discover new ‘druggable’ targets, identify novel drug candidates and validate their potency, sensitivity, specificity, PK, PD and even toxicity, metabolism and adverse drug–drug interactions in living subjects.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
The authors would like to thank colleagues in the Washington University Molecular Imaging Center for their insightful discussions contributing to this review. Supported by NIH P50 CA94056.
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