Pci using molecular tracers
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What is a Molecular Tracer?

A molecular tracer is a compound used for nuclear imaging, that is administered at a very low concentration. In order to trace activity, it's important that the concentration of the compound used doesn't affect the underlying biology. If you were to inject too much of an agent, it could start to change what's happening in the biological system.

You should be able to image at a low enough concentration that it doesn't affect the biology, yet you still get an image; this is known as the tracer principle. As most tracers have some kind of interplay with the biochemistry, cell receptors, molecular pathways and metabolic pathways, it means that we are able to investigate their paths using imaging techniques while keeping the concentration low enough so it doesn't interfere with those pathways and receptors. That's the traditional definition of a tracer, but what a tracer really consists of depends on the type.

Please outline the technologies involved with nuclear medicine imaging.

The imaging technology that is traditionally thought of when we talk about molecular tracers is positron emission tomography (PET) and single-photon emission computed tomography (SPECT).

PET and SPECT are most suitable for molecular detection in nuclear medicine imaging due to their high sensitivity. Other methods, such as MRI and micro-CT, could allow you to make some level of molecular detections, but their level of sensitivity is much, much lower.

What information can be learned about a disease by using Molecular Tracers?

If you're using a molecular tracer to evaluate disease, one of the most common uses is for diagnosis of disease. The most common clinical tracer that's used is FDG, fluorodeoxyglucose, which shows the researcher if there's abnormal glucose metabolism.

This would be considered a biomarker. The places that you might see a disruption or change of normal glucose metabolism would be in tumors that are rapidly growing, as they have higher metabolic activity.

This is a very common technique used to stage diagnostics in oncology, but there are other places you might expect high metabolic activity. We would consider glucose a metabolic biomarker in neurological diseases, for example Alzheimer's.

In neurodegenerative disease, you'd have disruption of normal glucose metabolism. In cardiology, we'd see changes in normal glucose metabolism. That is the most common one used in the clinic and preclinical.

It is also possible to use molecular imaging to look at preclinical research in tissue perfusion. Molecular imaging allows you to answer questions about the impact of disease on blood flow: is there a normal flow of blood in the heart? Is there a normal flow of blood in the brain or other tissue?

Therefore overall, tracers in molecular imaging can be used both clinically and in preclinical models when using it as a biomarker for disease.

What are the applications of PET and SPECT imaging with tracers in drug discovery?

You might use some of them as a biomarker; do I see the tumor metabolism increase or decrease with the metabolism? What's the mechanism of the drug activity? For example, if I'm using a drug that targets angiogenesis, I might use a tracer that tells me whether angiogenic markers are increasing or decreasing, which gives me an indication of the mechanism of the drug during preclinical research.

If I'm suspecting a mechanism, I might use a tracer that gives me an idea about the underlying molecular events that are occurring. It's also potentially used in neurological drugs. PET can be used to look at changes in very specific neurotransmitter levels, and looking at the neurotransmitter levels at different stages of transmission, presynaptic and postsynaptic.

If you want to look in vivo to try to determine the pathway and activity of a neuroactive or psychiatric drug and how it affects different neurotransmitters etc, you can look at this with PET or SPECT in vivo.

Please give an introduction to the Bruker instrumentation that uses PET and SPECT imaging for research in preclinical diseases.

Bruker have a family of PET products that can be divided into PET-CT and PET-MR. With PET technology, it has become common to have integrated systems because PET technology gives you very sensitive molecular detection, but it doesn't tell you much about anatomy. So, without an accompanying image that gives you a landscape for the molecular detection, you don't necessarily know exactly where the tracer is located.

Our registered PET-CT system is the AlbiraSi. We started with PET systems and PET-CT systems, and over the last five years or so, PET-MR systems have become more commonplace clinically, and now Bruker's leading the way in PET-MR development.

On the PET-MR side, we have both what we would call a sequential or in-line system, where the animal is first imaged in PET and then imaged in MR or vice versa; or an insert, where the PET system actually sits inside the MR field and you can make both acquisitions at the same time. There are some possible synergies for making the acquisitions simultaneously. You can collect data from both, and it might tell you more than simply doing a sequential and then having an image fusion.

Which preclinical disease models has the AlbiraSi been used to investigate and what information has it found about these diseases?

It's been used in studies of oncology, looking at different molecular events and genetic factors in disease in a range of different types of cancer. The AlbiraSi has also been used to evaluate different therapeutics and determining whether a change of metabolism/tumor growth is seen with or without a drug. Sometimes it's used for new combination therapy, combining what were traditionally single therapies, asking, if we combined two different therapeutics, does that improve the outcome?

The AbiraSi has also been used in a similar manner in neurological diseases and looking at possible therapeutics, such as Alzheimer's disease and other neurological disorders. There is a potential to also look at cardiology with the new PET-MR imaging systems, which will be a growing area for PET. The ability to combine those two things will improve the potential to do preclinical cardiology studies. Much of what has been accomplished or is ongoing, is validating new tracers, which includes developing more specific tracers.

How many types of Molecular Tracers are there? Are different PET Tracers needed to investigate different diseases?

There are a number of approved PET tracers. A lot of the research that you see in preclinical imaging is in the development of new tracers, validating new compounds. I'd estimate that 50% of what people are looking at on our systems is broken down into two things.

They're either using it as a biomarker to research disease in an established tracer, or the work is focused directly on developing a new tracer compound. The catalog of tracers that have been published is in the range of hundreds, if you look at all the different isotopes. That doesn't mean they're clinically approved, but they've been validated in research publications and peer review publications.

Infection is an area where there is currently a lot preclinical research into tracer development. In cardiology, tracers specifically for plaques may be explored, as well as more specific tracers for neurological disorders. There has recently been preclinical development of Alzheimer-specific tracers, some of which are now reaching the clinic.

Are Molecular Tracers easy to design? What happens if they are designed incorrectly?

I would say that molecular tracers are difficult to design, requiring a team typically comprising of a radiochemist, biologist, and an imaging specialist. Many teams will include these specialties to design and validate the tracer.

A tracer consists of a number of different components. Firstly, the molecule must have some kind of biomolecular activity that will allow it to integrate, be trapped in or bind a tissue.




Next, there's the labeling of the tracer, and selecting the most appropriate isotope to use. There's a lot of publications on new types of bioactive molecules, and what kind of isotope to label them with: F-18, Gallium-68, Zirconium-89 etc.

The final part of developing a new tracer, is determining what kind of chemistry to use bind the biomarker and the labelled isotope together.

If the tracer isn't effective, you might see nonspecific bindings, false positives and false negatives. There may be poor labelling of your compounds, resulting in a disintegration or metabolism of the compound.

Designing a molecular tracer is a very involved process from start to finish, including a lot of other technologies other than PET imaging, like radiochemistry, chromatography some amount of in-vitro validation and finally, in-vivo validation.

How do you decide which isotype to use?

One of the critical variables is the biodistribution time of the tracer. A smaller compound is going to typically reach the target faster than a larger molecule. For example, FDG glucose is an example of a very small molecule. With this, we can use F-18 which has some very useful properties, such as having a relatively short half-life, but not too short - the half-lives can range from seconds to days.

At the other end of the spectrum we have immuno-PET, which has become a trend in preclinical research. This involves using antibodies as your biomolecule. Antibodies are orders of magnitudes larger than glucose, and can take days to reach their destination.

Therefore, if an antibody is tagged with F-18 with that short half-life, by the time it reaches the target, the F-18 isotope activity is so decayed that you won't get much of a signal to produce an accurate image. Thus, there's interest in using longer half-life antibodies, or longer half-life nuclides and isotopes, that better match the biodistribution of the tracer.

Another aspect to consider is whether the isotope is appropriate for integrating into the molecules. The advantage of using an organic compound such as Carbon-11, is that it can be substituted into the backbone of the existing biomolecular structure. With other compounds, such as zirconium, it is not possible to integrate the molecules in this way.

Are there any limitations to using molecular tracers in preclinical research? How does it compare to other methods?

One of the key advantages in molecular imaging in general relative to other methods, is the strong emphasis on reducing the number of animals that are exposed to research protocols. Rather than imaging multiple cohorts of animals and sacrificing upwards of five times more animals, we can use the same animals from start to finish throughout the study to determine the same outcome, and sometimes in a better way.

Another advantage is that PET and SPECT has direct clinical translation. In order to validate a molecular tracer for clinical human use, you want to replicate what's happening in a live animal before you take that to the clinic.

Take optical imaging for example. Optical imaging is also a molecular modality, but it's largely for research and doesn't translate. There's no indication that we can use an optical probe and try to use it in a human, or at least not in the same way.

With in-vitro methods, you cannot get the best indication of what's going to happen when it's taken to the clinic unless its executed the same way preclinically. Imaging real-time biological pathways in vivo with PET and SPECT is a direct translation modality.

How do you see Bruker technology advancing the potential of molecular tracers in not only disease and drug discovery, but other applications too?

Bruker instrumentation is providing the tool for researchers to evaluate a lot of different disease models, and doing so in a way that reproduces what's happening in the clinic and what would be happening in a live sample.

The ability to look at live samples and disease models over time, using imaging methods that are directly translatable to clinical imaging, is what Bruker systems are enabling us to do.