Molecular imaging strategies for drug discovery and development

doi:10.1016/j.cbpa.2006.06.028

Current Opinion in Chemical Biology

Volume 10, Issue 4, August 2006, Pages 334-342

https://doi.org/10.1016/j.cbpa.2006.06.028 Get rights and content

Recent advances in non-invasive molecular imaging provide exciting opportunities for discovery, validation and development of novel therapeutics. As the arsenal of detection devices and strategies, injectable probes, genetically encoded reporters and animal models rapidly expands, molecular imaging is becoming indispensable for drug discovery and development. Not only do such strategies reduce the time, cost and workload associated with conventional destructive end-point assays, but they also enable spatial and temporal monitoring of in vivo gene expression, signaling pathways, biochemical reactions and targets as they relate to the pharmacokinetics and pharmacodynamics of novel drugs.

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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Molecular imaging strategies for drug discovery and development

Introduction

Section snippets

Choosing an appropriate imaging modality

Injectable drugs

Imaging genetically encoded reporters

Conclusions

References and recommended reading

Acknowledgements

Cancer Cell

Mol Imaging Biol

Nat Rev Drug Discov

J Nucl Med

N Engl J Med

J Immunol

Molecular imaging in drug discovery and development

Nat Rev Drug Discov

Reporter gene imaging: potential impact on therapy

Nucl Med Biol

Molecular optical imaging: applications leading to the development of present day therapeutics

NeuroRx

Scaling down imaging: molecular mapping of cancer in mice

Nat Rev Cancer

In vivo molecular-genetic imaging: multi-modality nuclear and optical combinations

Nucl Med Biol

Characterization of a gallium-67/gallium-68 radiopharmaceutical for SPECT and PET imaging of MDR1 P-glycoprotein transport activity in vivo: validation in multidrug resistant tumors and at the blood-brain barrier

J Nucl Med

P-glycoprotein deficiency at the blood-brain barrier increases amyloid-beta deposition in an alzheimer's disease mouse model

J Clin Invest

Imaging the pharmacodynamics of HER2 degradation in response to Hsp90 inhibitors

Nat Biotechnol

Subtractive proteomic mapping of the endothelial surface in lung and solid tumours for tissue-specific therapy

Nature

Pathology: cancer cells compress intratumour vessels

Nature

Cell-specific targeting of nanoparticles by multivalent attachment of small molecules

Nat Biotechnol

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Mol Cancer Ther

Molecular and cellular imaging of atherosclerosis: emerging applications

J Am Coll Cardiol

Synthesis and characterization of a small, membrane-permeant, caspase-activatable far-red fluorescent peptide for imaging apoptosis

J Med Chem

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Proc Natl Acad Sci USA