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.