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Molecular imaging in drug development

Key Points

  • Drug development is a costly, time-intensive and high-risk endeavour, with only two to three approvals for novel therapeutics in new drug classes per year eventually making it to market. New strategies are required to identify promising new drug candidates early on and, likewise, to terminate those candidates that are unlikely to be successful, thus allowing a more rapid and efficient move to pivotal trials.

  • Molecular imaging attempts to characterize and quantify biological processes at the cellular and subcellular level in intact living subjects. It exploits specific molecular probes and intrinsic tissue characteristics as the source of image contrast, providing the potential for understanding of integrative biology, earlier detection and characterization of disease, and evaluation of treatment.

  • As most molecular imaging techniques are routine in clinical radiology departments and have counterparts in the experimental research setting, it is possible to design preclinical experiments that not only predict clinical imaging observations but also provide a mechanistic understanding of the observed biological response.

  • Molecular imaging has the potential to have a significant impact on different phases of drug development, including target expression, compound screening and optimization, as well as Phases I to III clinical studies. Examples are detailed in the text of the article.

  • The option of an exploratory IND (eIND) initiated by the US Food and Drug Administration enables first-in-human molecular imaging studies to be performed with reduced preclinical support as compared to that required for a full IND.

  • Consortia such as the Alzheimer's Disease Neuroimaging Initiative, the American College of Radiology Imaging Network and the High-Risk Plaque Initiative seek to correlate a number of imaging biomarkers with the clinical manifestations of diseases and, if successful, will greatly increase the inclusion of these imaging techniques in exploratory clinical development of novel therapeutics.

Abstract

Molecular imaging can allow the non-invasive assessment of biological and biochemical processes in living subjects. Such technologies therefore have the potential to enhance our understanding of disease and drug activity during preclinical and clinical drug development, which could aid decisions to select candidates that seem most likely to be successful or to halt the development of drugs that seem likely to ultimately fail. Here, with an emphasis on oncology, we review the applications of molecular imaging in drug development, highlighting successes and identifying key challenges that need to be addressed for successful integration of molecular imaging into the drug development process.

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Figure 1: Molecular imaging and the drug development process.
Figure 2: A summary of modalities used for molecular imaging.
Figure 3: Complementation-based molecular imaging approach for studying drug-mediated protein–protein interactions in cell culture and in living animals.
Figure 4: High-throughput molecular imaging of oestrogen receptor–ligand interactions in vitro, in cell culture and in living subjects.
Figure 5: Molecular imaging of tumour characteristics.
Figure 6: A flow chart showing how different molecular imaging strategies can be integrated into different parts of the drug development pipeline.

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Acknowledgements

We would like to acknowledge the support of the Swiss Foundation of Medical-Biological Grants (J.K.W.), the Novartis Research Foundation (J.K.W.), the Swiss Society of Radiology (J.K.W.), as well as the support of NIH grants ICMIC CA114747 P50 (S.S.G.), CCNE U54 CA 119367 (S.S.G.), R01 CA082214 (S.S.G.), R01 HL078632 (S.S.G.), Doris Duke Foundation (S.S.G.), and the Canary Foundation (S.S.G.).

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Correspondence to Sanjiv S. Gambhir.

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Competing interests

S.S.G. is on the advisory board for Centella, Chiron, CTI/PetMet Pharmaceutical Inc., Endra, Enlight, Genetech, General Electric, GlaxoSmithKline, Henry Ford Health Systems, Lumen Therapeutics, MediGene Inc., Philips Medical Systems, Plexera, Varian Medical Inc., VisualSonics. He has served as a consultant for MediGene Inc., Millennium, Philips Medical Systems and Spectrum Dynamics. He has received grants from Alza, Bayer Schering, the Department of Energy, General Electric. He has had industrial research collaboration with GlaxoSmithKline, Nova R&D, Pfizer, RMD Inc. He has stocks with Endra, Enlight, Pfizer, Spectrum Dynamics, VisualSonics, and received honorarium from Siemens. N.V.B. is affiliated (employee) with Genentech. This manuscript refers to some Genentech products. L.M.D. is an employee of Bayer Schering Pharma.

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A summary of imaging modalities (PDF 155 kb)

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FURTHER INFORMATION

Alzheimer's Disease Neuroimaging Initiative

American College of Radiology Imaging Network

Guidance for Industry, Investigators, and Reviewers Exploratory IND Studies

High-Risk Plaque Initiative

Molecular Imaging and Contrast Agent Database

Glossary

Investigational new drug application

Before initiating any clinical trials of a new drug in humans in the United States, a drug sponsor must submit an investigational new drug application (IND) to the US FDA. The IND contains three broad categories of information: data from animal pharmacology and toxicology studies, manufacturing information, and clinical protocols and investigator information.

Tumour xenograft

Tumour specimens can be grown in immunocompromised rodents to provide tumour models with many of the complexities of human tumours.

Luciferase

The luciferase assay is a method to detect the presence of ATP based on the ability of the firefly enzyme luciferase to catalyse a reaction between its substrate luciferin and ATP, releasing the two terminal phosphate groups of ATP. Luciferin becomes excited during the process and, on return to its basal state, releases energy in the form of light.

Metabolic flare

Metabolic flare corresponds to an increase of radiotracer uptake (for example, FDG) in tissue (for example, in a tumour) following radiotherapy, hormonal therapy or chemotherapy. Possible causes for this phenomenon include post-therapeutic inflammatory reactions, increased energy utilization related to induction of apoptosis, or partial agonistic effects of hormonal therapy (for example, during anti-oestrogen therapy in breast cancer).

Bio-isosteric substitution

The substitution by a radiolabel of similar size, electronic configuration and lipophilicity for a portion of the parent drug molecule.

Pharmacophore

The steric and electronic features of a ligand that are necessary to ensure optimal interactions with a biological target structure and to trigger (or to block) its biological response.

Chelating agent

A molecule that has the capacity of tight metal binding (complexation).

Clinical end point

A clinical end point assesses how a patient feels, functions or survives.

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Willmann, J., van Bruggen, N., Dinkelborg, L. et al. Molecular imaging in drug development. Nat Rev Drug Discov 7, 591–607 (2008). https://doi.org/10.1038/nrd2290

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