Molecular Imaging in Drug Development

Increased prevalence of age-related illness calls for new drugs

Drug Development

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While healthcare has made significant advancements over the last century, and medical professionals are more equipped than ever with the tools to treat a whole range of illnesses, the landscape of healthcare continues to evolve, and with this ever-changing environment comes the continued need for new drug candidates.

Statistics show that diagnosis of cancer is increasing, as is the rate of metabolic diseases and neurodegenerative disorders, all of which are considered to be strongly linked to the fact that most of us are now living longer.

With the rising prevalence of significant age-related illnesses, the healthcare sector is demanding the development of new drugs to help improve treatment outcomes and healthy life expectancy.

Molecular imaging has provided scientists with a tool for improving and accelerating the drug development process.  This technique enables the non-invasive visualization of the biological and biochemical impact of drugs in living patients.

Molecular imaging allows scientists to deepen their understanding of how certain drugs impact on disease, helping to inform their decisions about which drugs are the best candidates for new therapies, and which may have disadvantages or will be likely to fail.

In particular, drug development for new cancer treatments relies heavily on molecular imaging to guide it. Below we discuss how molecular imaging works, how it is applied to drug development (specifically for cancer), and what are the future challenges that need to be addressed to improve the use of molecular imaging in drug development.

What is molecular imaging?

Methods to conduct molecular imaging can vary, but essentially involve the visualization, characterization, and measurement at the molecular and cellular level of processes occurring in living systems, such as humans. As a standard, molecular imaging incorporates either two or three-dimensional imaging along with quantification over time.

Techniques to achieve molecular imaging may include but are not limited to, radiotracer imaging/nuclear medicine, optical imaging, MRI, MRS, and ultrasound. In the field of drug development, molecular imaging is used to track the activity of a candidate drug and visualize its interactions with specific molecules and biological pathways within the body.

Applications in drug development

Molecular imaging is used to visualize the effect of a candidate drug on cancer metabolism, which can inform medical professionals on the status of the tumor. It is well known that the metabolic profile of cancerous cells includes the increased consumption of glucose and glutamine, as well as alternations in the use of metabolic enzyme isoforms, increased glycolysis, and increased secretion of lactate.

PET imaging can visualize these metabolic pathways, most often utilizing the FDG tracer, the most widely used tracer in oncology. PET imaging allows scientists to see how tumors respond to candidate drugs that are being developed. Studies have shown that FDG–PET correlates with patient survival in certain circumstances, meaning that it can be used to test the effectiveness of a new drug.

Tumor proliferation is a key indicator of how the disease is progressing, and how it is responding to treatment. Imaging can visualize, monitor, and measure tumor proliferation, allowing for the evaluation of the effectiveness of candidate drugs. 18F- labeled thymidine analog 3′-deoxy-3′-fluorothymi- dine (FLT) is a commonly used proliferation marker often used in conjunction with FDG imaging. FLT is phosphorylated by the enzyme thymidine kinase, and it is subsequently incorporated into the DNA of cells, where it can be measured by FDG-PET.,   As its levels are proportional to kinase activity it can be used as a quantitative marker of cell proliferation.

Apoptosis is the process of programmed cell death which is part of the normal life cycle of a cell. Cancer cells, on the other hand, are characterized by their aversion to this process. Using molecular imaging scientists can visualize and measure the effect of drugs that aim to induce apoptosis in cancer cells.,

An increase in angiogenesis, the process through which new blood vessels form, is a hallmark of cancer as growing tumors need an increased blood supply to support their proliferation. Anti-angiogenic drugs are being designed that target molecular effectors of angiogenesis such as VEGF and its receptor VEGFR, matrix metalloproteinases (MMPs), and αvβ3 integrin.

Scientists use molecular imaging to evaluate the effectiveness of candidate anti-angiogenic drugs by visualizing and monitoring their interactions with these molecular effectors.

Hypoxia is an important feature of tumors, it predicts key factors such as radio-resistance, and increases resistance to drug treatment. Also, it promotes angiogenesis and metastasis. Molecular imaging is being used to visualize hypoxia to help guide radiation treatment and chemotherapy to the right location. It can also be used to monitor the effectiveness of these kinds of treatments against cancer.

Future challenges

While molecular imaging is widely used in preclinical and clinical studies during drug development for cancer and other illnesses, several main challenges still need to be addressed.

Firstly, imaging biomarkers need to be able to reliably assess some form of biological activity of the candidate drug to infer clinical effectiveness. Also, the biomarker must be cost-effective to be feasibly adopted at a wide scale, but its correlation to a clinical outcome often needs to be validated in expensive and time-consuming clinical trials.

Finally, molecular imaging techniques still need to be further developed to be able to provide single-cell resolution at any given depth.

Sources:

Cunha, L., Szigeti, K., Mathé, D., and Metello, L. (2014). The role of molecular imaging in modern drug development. Drug Discovery Today, 19(7), pp.936-948. https://www.sciencedirect.com/science/article/pii/S135964461400004X

Rudin, M. and Weissleder, R. (2003). Molecular imaging in drug discovery and development. Nature Reviews Drug Discovery, 2(2), pp.123-131. mbpl.bmes.nthu.edu.tw/.../...0drug%20discovery%20and%20development.pdf

Willmann, J., van Bruggen, N., Dinkelborg, L. and Gambhir, S. (2008). Molecular imaging in drug development. Nature Reviews Drug Discovery, 7(7), pp.591-607. https://www.nature.com/articles/nrd2290#citeas

Bellantuono, I., Potter, K. P. (2016). Modeling aging and age-related disease. Drug Discovery Today: Disease Models, 20, pp.27-32.

https://www.sciencedirect.com/science/article/pii/S174067571730035X

Peck M., Pollack H., Friesen A., Muzi M., Shoner S. C., Shankland E. G., Fink J. R., Armstrong J. O., Link J. M., Krohn K. A. Applications of PET imaging with the proliferation marker [18F]-FLT. The Quarterly Journal of Nuclear Medicine and Molecular Imaging, 59(1), pp95-104.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4415691/

Further Reading

Last Updated: Feb 4, 2020

Sarah Moore

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Sarah Moore

After studying Psychology and then Neuroscience, Sarah quickly found her enjoyment for researching and writing research papers; turning to a passion to connect ideas with people through writing.

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