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The use of nuclear and optical molecular imaging in drug development

Prof. G.M. van Dam, MD, PhD

Molecular imaging obtains detailed images of a body’s internal disease processes at the molecular and cellular level. It supports physicians in making earlier and more precise diagnosis than often possible with other types of medical imaging. For instance, conventional X-ray and CT scans only provide information about anatomical and morphological changes. Additionally, molecular imaging can be used to image therapy response in a more detailed manner. However, the use of molecular imaging extends beyond patient diagnosis and treatment. Namely, due to its precise nature it can be used to visualize the efficacy of new drugs or treatments, like immunotherapy, in vivo. This offers many benefits for drug developers that are trying to get new drugs on the market.

There are two main types of molecular imaging: nuclear and optical. Both methods use an imaging device and imaging agent/tracer. Nevertheless, the nature of these tools is significantly different. In addition, both imaging modalities offer different benefits to drug developers actively involved in clinical trials.

What is nuclear molecular imaging?

Nuclear molecular imaging uses radionuclides coupled to a targeting agent as an imaging agent to visualize the biological process of interest in the body. In many diseases specific biochemical processes or receptors are upregulated and can be used as a marker for disease activity. By selecting a ligand that is specifically metabolized by this biochemical process or targets the receptors the disease activity can be targeted. By labelling this ligand with a radionuclide, resulting in a radiotracer, it can be traced in the body by radionuclide imaging cameras. The most widely used cameras are Positron Emission Tomography (PET) and Single-Photon Emission Computed Tomography (SPECT).

The advantage of using nuclear molecular imaging is that it provides information that cannot easily be obtained with standard radiology imaging techniques (e.g. CT or MRI). For example, in treatment monitoring of cancer where the treatment does not initially result in shrinkage of the tumour, but in a strong reduction in biochemical processes. By measuring tumour volume only by CT or MRI, it can then be incorrectly concluded that the therapy is not having an effect while by using PET or SPECT-imaging a treatment effect would be observed.

What is optical molecular imaging?

Generally optical molecular imaging is generated either by a fluorescent or bioluminescent light source. These light sources are designed to visualize the tissue of interest. The technique covers mesoscopic imaging in animals and humans, with the exception of bioluminescence, which can only be used in animals. In other words, optical imaging extends in the range from macroscopic to microscopic imaging. Practically, as is the case in fluorescence imaging, the targeted fluorescent tracer attaches itself to specific molecules. For example, receptors on the surface of cancer cells. In turn, when excited with an external applied light source, the fluorescent tracer emits light. Consecutively, the tumour or disease state becomes visible. The light used for optical fluorescent imaging can have a wavelength from the visible light spectrum into the far near-infrared (NIR) or even NIR-II wavelengths.

Unlike nuclear molecular imaging, optical molecular imaging produces superficial 2D images. Nevertheless, it is also able to capture the signal intensity and biodistribution over time in small animal imaging camera system setups using tomographic techniques. Additionally, although it has a limited penetration depth, it delivers high resolution images.

A comparison of Nuclear and Optical Molecular Imaging

Nuclear and optical molecular imaging in drug development.

In the current drug development environment nuclear molecular imaging is more widely used than its optical variant. However, also this is still on a limited scale and more often used for animal models than actual in-human studies. In other words, there is a large untapped advantage for drug developers to employ nuclear and optical molecular imaging in their early phase in-human proof-of-concept clinical trials. Foremost, it offers great opportunities for early precision drug development. Additionally, it is beneficiary for patient stratification in subsequent phase II and III clinical trials. It elucidates the presence of the target of interest prior to instalment of a smart drug, such as immunotherapy. Thus, instead of treating individual patients as a group, molecular imaging provides a precision medicine tool as a priori diagnostic and response measurement tool for each unique patient.

The first step to use molecular imaging in clinical trials is to label the New Molecular Entity (NME) or therapeutic drug with a radionuclide or fluorescent dye. Next, an animal single-dose extended toxicity study needs to determine if the labelled compound is safe to use in humans. A positive result is followed by systemically administering a microdose of the GMP-produced drug into subjects with the disease target present – also called the target population. After intravenous injection of the labelled drug to the subject, the drug-label conjugate can be detected in vivo and ex vivo using dedicated nuclear or fluorescent imaging camera systems. You can read more about the microdosing process here or watch our recent webinar on microdosing.

The benefits of molecular imaging in drug development.

The main advantage of using a nuclear imaging technique like PET is that it has a very high sensitivity. In addition, it has the ability for whole-body imaging. These characteristic result in true quantification of the presence of the labelled compound in various organ systems and the diseased area of interest in time. This implies that low concentrations of a radionuclide can be detected, and thus, administered. In turn, this means that there is a low radiation exposure, which creates the possibility of repeated imaging procedures in time with the radioactive tracer. Consequently, biological processes in the body can be studied without saturating the molecular process itself in a spatiotemporal fashion.

Another benefit of PET is that it generates 3-dimensional images that show the distribution of the drug throughout the body. In combination with the high penetration depth in tissue, PET is particularly suited for the effect of ‘the drug on-lesion’ seated deep in the body. This is currently not be possible with fluorescence imaging in humans. Furthermore, PET allows for accurate quantification of the radiotracer in deep seated tissues like the liver and kidney.

Optical molecular imaging offers different benefits than nuclear techniques. Foremost, it does not expose patients to ionizing radiation, as it is based on non-ionizing radiation (light). This implies less costly infrastructures and facilities for labelling the NME either GLP or GMP, with great flexibility of transportation and storage of fluorescent labelled compounds to be used in multicenter studies, which can be more challenging in nuclear imaging techniques. Due to the safety and speed of optical imaging it can be used for lengthy and repeated procedures over time. Thus, it allows for the monitoring of a fluorescent labelled drug’s tissue distribution in time.

Furthermore, researchers can take advantage of the wide range of the wavelength of light in order to see and measure many different properties (i.e. fluorescent tracers) of an organ or tissue at the same time. This is also referred to as a multispectral fluorescent imaging methodology. Other imaging techniques are limited to just one or two measurements. They often don’t have the ability to highlight affected and non-affected tissue with two or more different wavelengths. Additionally, by using sophisticated spectroscopy instruments true quantitative measurements can be taken at the surface of the tissue of interest. For example, in fluorescence molecular endoscopy and skin diseases.

The largest advantage of both molecular imaging modalities is that they enable scientists and drug developers to make early go/no-go decisions based on accurate in-human imaging data of their labelled drug compound. This way, companies can decide in an early phase of the drug development process which compound has the highest efficacy (on-target characteristic) or highest chance of side-effects(off-target characteristic) before larger investments are needed. Consequently, this will save significant time and monetary resources.

In the end, it is not a question of which molecular imaging technique is better. Instead, it should be about which one fits best with the primary goals of the clinical trial. Additionally, as both modalities offer different information to a drug developer, they can be used in a hybrid form. Ultimately, they are not competing, but are complementary to one another.

At TRACER, we specialize in designing both nuclear and optical molecular imaging studies to accelerate drug development. You can read more about our expertise here.


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