Contributing author: Martin Schain, Director PET Imaging @ Antaros Medical
It is an exciting time for Positron Emission Tomography (PET) imaging in clinical research. While it is more commonly used in oncology and Central Nervous System (CNS) research, PET can also provide value in studies of metabolism and metabolic disease.
While PET imaging is indeed complex, it is also highly adaptable and flexible to answer specific research questions that are difficult, if not impossible, to answer using other methods.
This blog post will briefly describe PET imaging and some of the main ways it can be used in dug development clinical trials. Further, some recent developments in the field will be discussed, as will what these could mean for PET within a clinical trial setting.
What is PET imaging?
PET is an imaging method that utilises an injected radioactive tracer to visualise various processes in the body. Put in simple terms, a radionuclide (label) is attached to a target molecule, creating a radiotracer (sometimes referred to as “tracer” or “radioligand”) that is injected into the subject. The PET scanner detects the radiation emitted by the radionuclide, and this signal is turned into an image that depicts the tracer’s concentrations throughout the body. The information obtained from this image depends on the properties of the tracer and the physiological functions in the body.
PET imaging can help to answer various questions throughout drug development. Here we borrow those posed by Matthews et al. as examples:
- Does a new drug molecule reach the tissue of interest in potentially pharmacologically active concentrations?
- Is it interacting with the target of interest?
- What is the quantitative relationship between the extent of this interaction and the administered dose?
- What are the consequent pharmacological effects and how long do they last?
There are a multitude of available PET tracers for many different targets in the body. The research questions of interest will determine which tracers should be used and how the imaging protocol should be designed.
All the radionuclides used for PET tracers result in the generation of a positron when they decay. When that positron collides with a local electron, two photons (light particles) are created and travel in opposite directions, separated by 180°. The photons propagate through the body and are eventually detected by the PET system. The timing and coordinates of this ‘hit’ will reveal the location of the decay, and all the occurrences measured throughout the scan can be reconstructed into an image revealing the spatial and temporal distribution of the tracer. Radiolabelled tracers are designed to interact selectively with different targets of interest.
PET imaging has very good sensitivity for detecting signal from the tracer. However, it is currently necessary to combine PET with other imaging modalities, such as computed tomography (CT) or magnetic resonance imaging (MRI), to provide anatomical reference and other information that helps to ensure the images are being interpreted correctly.
Examples of types of PET imaging studies in drug development
The use of PET imaging in research is versatile, and the same technology/tracer/protocol can be used to answer different research questions. Perhaps for this reason, there is no established consensus on how to classify PET applications in clinical trials for drug development.
Here I describe the following examples based on my experience, knowing that there will be both exceptions to and overlap between these buckets:
Substrate metabolism studies
The first type of PET studies for drug development that we will discuss in those that look at substrate metabolism. This application is already used in many different disease areas including oncology and cardiovascular diseases (CVD), but can also provide valuable information in metabolic diseases like obesity and type 2 diabetes (T2D).
In substrate metabolism studies, a radiolabelled analogue of the actual substrate is injected, and the scan provides information regarding how much of, and depending on the protocol, how quickly, the substrate is utilised in the cells. A high signal in a particular organ is then interpreted as a high metabolic rate of that particular substrate in that particular organ.
The most commonly used PET tracer is [¹⁸F]-fluorodeoxyglucose (FDG), which is used to assess glucose metabolism across several applications in cardiac, brain, and tumour metabolism, as well as in metabolic diseases. Other tracers can be used to look at metabolism of different substrates like fatty acids, and to a lesser extent; ketone bodies.
Target engagement studies
Target engagement studies are performed to verify that a drug is binding to the intended target in vivo. This is of particular importance in early clinical development programs, as failure to reach or sufficiently bind to the target is a common reason for failure in clinical drug trials. In addition, target engagement studies can provide insights to support mechanism of action hypotheses and to put into context treatment responses. Traditionally, in PET target engagement studies, each subject is first scanned at baseline, and then again after the drug has been administered. The difference in tracer uptake between the baseline and second scan is then used to determine occupancy, i.e., the proportion of the available targets that are occupied by the drug at the time of the second scan.
Performing target engagement studies is much more straightforward if there is an existing or established tracer for the target of interest. In these cases, the drug development program can instantly advance to a clinical trial to assess the target engagement and dose-response relationship for the drug.
For many (most) targets in the body, however, there is no existing radiotracer. Although target engagement studies are possible even when there are no radiotracer available, the process becomes much more complicated. Either a new tracer (that is chemically distinct from the drug) needs to be developed, or a radionuclide (e.g., ¹¹C or ¹⁸F) can be added to the drug itself, which then acts as the tracer molecule.
It is worth noting that the process of developing a PET tracer can be long and resource-intensive, as the suitability of the tracer needs to be carefully assessed before it can be used in clinical trials. For example, the molecule needs to bind relatively quickly, as the decay of the radionuclide only allows for imaging during a certain time window following injection.
Pharmacokinetic (PK) studies
The next type of PET imaging study is pharmacokinetic studies, often referred to as ‘PK’ studies. These studies look at the absorption, distribution, and elimination of the drug. This information can then be used to draw insights about dosing, toxicity, and the likelihood of therapeutic success.
Typically, PK studies are associated with measuring the concentration of the drug in plasma. In most cases it is the drug concentration in tissue or organs of interest that induces the therapeutic effect, and this concentration often differs from the plasma concentrations. By radiolabelling the drug itself and looking at both plasma kinetics and drug concentrations in specific tissues and organs, a better overall understanding of the drug pharmacokinetics can be determined. The addition of PET PK studies is especially impactful in cases where uptake of the drug is hypothesised or desired within certain tissues or organs.
In PK studies, the selection of radionuclide is particularly important, as it needs to match with the biological half-life and time window of interest for the drug itself. In this context, the recent development of using isotopes with long half-lives (e.g., ⁸⁹Zr) is particularly useful in combination with long-acting large molecules, as it can be used to radiolabel e.g., antibodies and visualise drug distribution more than a week after treatment.
Pharmacodynamic (PD) studies
Finally, PET studies can be used to look at the downstream effects or biological processes related to the administration of the drug. These are called pharmacodynamic or ‘PD’ studies. the possibilities for studies of this type are vast.
Here there is also room for overlap with the other study types previously discussed. For example, a PD study can be linked to substrate metabolism if the drug is believed to affect e.g., energy expenditure. This is most commonly done with [¹⁸F]-fluorodeoxyglucose (FDG), but other radiolabelled substrates are also feasible. PD studies can also be, and often are, linked with PET PK studies. For example, when determining dosing it is important to determine the optimal dose at which therapeutic effect and undesirable side effects are best balanced.
The future of PET imaging: what could it look like?
Although PET imaging provides unique opportunities to assess drug interactions and their downstream effects in a living human, it does come with some limitations. The technology can be expensive and time-consuming, and its use should be thoughtfully considered as it exposes subjects to ionising radiation. In this context, there are several exciting recent developments in the field that I think may have an impact.
Total body PET/CT scanners
A major limitation of current PET scanners regarding their use in metabolic research is their limited field of view (FOV). As described above, the strength of the PET signal relies on the detection of the photon pairs. The photos can travel at angles that mean they escape the PET system without hitting the detectors, as shown in the figure below.
Over the years, there have been increases in the FOV of commercially available scanners. The latest generation of PET systems, so-called “total body PET scanners”, covers an exceptionally large FOV. There currently exist 3 different commercially available total body PET/CT scanners; the uEXPLORER, the PennPET Explorer, and the Biograph Vision Quandra. Providing detailed descriptions of the scanners is beyond the scope of this article, I will instead point the dedicated reader to Nadig et al. and Katal et al., who provide some nice reviews. Instead, I will, however, briefly discuss two of biggest advantages I foresee in using these scanners in the clinical trials in a drug development setting.
By adding more detectors and increasing the field of view, total body PET scanners will have significantly increased sensitivity. This has several important implications. It means that a sufficient signal can be detected even at low radioactive doses, which in turn can mean less radiation exposure for subjects (i.e., a lower dose of radiotracer can be used without compromising image quality), and/or the possibility of detecting signal over an extended time window to meet the necessary dynamic ranges.
Furthermore, as large parts of the body are covered by the FOV in total body PET scanners, this opens the possibilities for looking at systemic diseases (e.g., type 2 diabetes and obesity), by studying multiple organs simultaneously. Several disorders, including metabolic diseases, involve multiple organs in complex disease states, and the possibility to image them and their interactions at the same time adds substantial value.
It is worth commenting that to date there are only a few of these scanners, this the availability of this technology is not yet widespread. I do believe that we will soon see these advantages and potential implications filter into clinical trials.
PET displacement studies
As was mentioned before, another limitation to widespread implementation of PET imaging studies in drug development is the cost per patient and the radiation exposure for subjects where multiple PET scans were required. An exciting development in the context of PET target engagement studies is a framework of models that can be used to determine occupancy from a single PET displacement scan.
Instead of the traditional design for target engagement studies (e.g., tracer administration, a baseline scan, drug + tracer administration, and then a second scan), PET displacement studies involve drug administration during the course of a single PET scan. There are several advantages to such a PET displacement study design. As each subject will only require one PET scan, they will be exposed to only one dose of ionising radiation. This will lower the cost per patient, and reduce unwanted variance in the data, enabling a more reliable estimation of occupancy. A publication utilising this method was just recently published.
To summarise briefly what has been discussed:
- Just like any other advanced technique, PET requires special knowledge and expertise and can seem complex but can also be useful in answering a range of research questions, particularly throughout drug development
- There are several types of PET imaging studies that can be used in clinical trials for drug development (and in metabolic disease), such as substrate metabolism, target engagement, pharmacokinetic (PK), and pharmacodynamic (PD) studies.
- Recent developments including total body PET/CT scanners and PET displacement studies will have important implications for the future use of PET imaging studies in drug development.
The views and opinions expressed in this article are solely those of the contributing author/s. These views and opinions do not necessarily represent those of Antaros Medical.
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