The Power of Positrons: PET/CT Advances Preclinical Pharmaceutical Research

Over the last five to ten years, multi-modal imaging has become established as a significant component of a preclinical researcher’s analytical toolbox, with its origins proven in drug discovery and development and routine human diagnostics.

Here, we highlight perhaps the most used and certainly the most sensitive and quantitative of these imaging modalities, the combination of positron emission tomography (PET) with X-ray computed tomography (CT), or PET/CT.

• PET is used to visualize molecular processes in the body: the system detects pairs of gamma rays emitted indirectly by a positron-emitting radioligand, which is introduced into the body on a biologically active radioactive tracer.
• A CT scan makes use of computer-processed combinations of many X-ray measurements taken from different angles to produce cross-sectional images of specific areas of a scanned object. In the clinical space these technologies enable the user to see inside the human body without surgery

The resulting co-registered images provide essential knowledge to help bridge the preclinical/ clinical boundary, the point at which preclinical evidence is considered sufficient to merit advancing a new drug candidate into first-in-human clinical studies.

A brief history of imaging

Early developments in imaging were focused on human clinical applications. In the 1950s, physicist Gordon Brownell and neurosurgeon William Sweet created a system that was used to detect brain tumors. Around twenty years later, the first PET camera was built for human studies by Edward Hoffman, Michael M. Ter-Pogossian, and Michael E. Phelps at Washington University. Phelps, who is often credited with inventing PET, received the 1998 Enrico Fermi Presidential Award for his work. Important technical developments, including significant refinement of radiotracers, detectors and instrument geometry, produced a series of improved instruments, and these early developments have been extensively discussed.¹

Researchers working within the pharmaceutical industry were quick to realize that imaging technologies could be applied to drug development. These technologies have the potential to enhance understanding of disease and inform better decisions on selecting the candidates that seem most likely to be successful or to stop the development of drugs for which failure is probable.

Theory and practice

PET creates three-dimensional (3D) images of a subject using radioactive tracers – molecules bound to a radioactive isotope – that are usually injected intravenously. The carrier molecule can bind to specific proteins, receptors, and biomolecular pathways in the body, to quantify a specific biological activity.

The radioactive isotope, commonly fluorine-18 (¹⁸F) or carbon-11 (¹¹C), produces positrons that interact with the surrounding electrons, resulting in the annihilation of both particles and the release of two photons (gamma rays). These photons emit in opposite directions (~180°) and are picked up by detectors in the PET scanner to map the radionuclide distribution in the body.

Successful drug development relies on the ability to understand dynamic biological processes in a holistic manner, including gene expression, enzyme and protein activity, progression and treatment of diseases, biodistribution, and pharmacokinetics/pharmacodynamics of new drugs. The multi-modal imaging approach of PET/CT provides a method to both map the path of drugs throughout the body over time, and to monitor efficacy and establish suitability for clinical use. Selection of the most appropriate imaging approach within the scope of drug development is based on similar questions you would encounter when applying the technology in the clinical realm.

Relevant technical considerations include sensitivity, spatial resolution, temporal resolution, target specificity and biodistribution of the contrast agent. One significant concern is to ensure that the signal reflects tissue phenotype rather than primarily reflecting blood flow, vascular permeability, or other variables that can influence tracer uptake. Practical considerations include cost, availability, and safety.

Powerful data in oncology

Preclinical researchers are interested in understanding the biology of tumor development, response to cancer treatment and drug toxicity. Imaging technologies such as PET/CT can shed light on the mechanisms of progression for different tumor types, and how treatment affects them.

Many cancers are associated with a higher metabolic turnover than normal cells. Using PET coupled with an injected radiolabeled glucose analogue tracer such as ¹⁸F-fludeoxyglucose (¹⁸F-FDG), glucose uptake can be quantified, and tumor burdens detected. This method can also be used to identify molecular biomarkers to contribute to cancer detection and the assessment of treatment response. PET/CT is used to determine the accumulation regions of ¹⁸F-FDG which are used to create a semiquantitative standardized uptake value (SUV) that assists in the diagnosis of tumor malignancy. Blood flow is another important marker, as tumor vascularization can potentially discriminate between nonneoplastic and neoplastic lesions.

Cancers are often targeted with combination drug therapies. Treatment regimens can address multiple molecular targets, as well as reducing the chance of drug resistance. One study used preclinical PET/CT imaging to monitor ¹⁸F-FDG tumor uptake for different treatment combinations: radiotherapy (Rad) alone, Rad + Temozolamide (Tmz), Rad + Mifepristone (Mife), and Rad + Mife + Tmz.² All data was acquired using a multi-animal transport system on a tri-modal small-animal PET/SPECT/CT system (multi-animal transport system (MATS) and Bruker Albira II, Bruker Biospin GmbH).

Rad + Tmz is the typical treatment regimen for glioblastoma, but the study found that using Mife as a priming agent suppressed tumor growth more than the other treatment combinations (Figure 1). The mechanism of this chemo-radio-sensitizing effect of Mife is yet to be fully characterized, but studies such as this help researchers make important steps towards improving available cancer treatments.

Figure 1. PET/CT images showing ¹⁸F-FDG tumor uptake, in four treatment combinations, at the beginning of treatment and 25 days later. Red arrows indicate tumor location at baseline and day 25, green arrows show sites of typical ¹⁸F-FDG uptake in brown adipose tissue (BAT). Reproduced from reference [3] in accordance with the Creative Commons License (https://creativecommons.org/licenses/by/2.0/).

Imaging adds value throughout preclinical drug development

Developments in PET/CT imaging continue to enable physiological, pharmacological and biochemical measurements that add value at every stage of preclinical drug development. Our basic understanding of a target disease is advanced, and important markers of disease development and therapeutic effectiveness are being revealed and can be monitored. The power of nuclear molecular imaging with today’s advanced instrumentation allows pharmaceutical researchers to progress potential drugs through preclinical studies, informing faster and more efficient development of future therapies.

References

1. Jones T and Townsend D (2017) History and future technical innovation in positron emission tomography. J Med Imaging (Bellingham). 4(1):011013. doi:10.1117/1.JMI.4.1.011013.

2. Llaguno-Munive M, Medina LA, Jurado R, Romero-Piña M, Garcia-Lopez P (2013) Mifepristone improves chemo-radiation response in glioblastoma xenografts. Cancer Cell International. 13:29. https://doi.org/10.1186/1475-2867-13-29.

About the Author

Todd Sasser, Ph.D is a Head of Applications for Bruker Preclinical Imaging. Dr Sasser studied at The University of Liverpool and The University of Hawaii and was a visiting scholar at The University of Notre Dame.