New PET method may pave the way for improved diagnostics

Antibody-based positron emission tomography (PET) is a novel approach to visualising disease-related proteins in the brain. The method holds considerable promise, but has so far been limited by the difficulty antibodies have in crossing the blood–brain barrier, as well as the need for long-lived radionuclides that generate the signal during scanning.

The research group has previously developed methods that enable the transport of antibodies across the blood–brain barrier. In the new study, a method that circumvents the limitation associated with long-lived radionuclides was shown to work in mouse models. The idea is to first deliver the antibody to the brain and then, in a separate step, introduce the radionuclide.

“Antibodies are taken up slowly and remain in the patient for a long time. If a radioactive substance is added at the initial stage, it means that patients also carry that substance in their bodies for an extended period. This is precisely the issue we are trying to address with this new method,” explains Sara Lopes van den Broek, Associate Senior Lecturer at the Department of Public Health and Caring Sciences.

“The problem, put simply, is that patients cannot walk around being radioactive for several days while waiting to undergo brain imaging,” says Stina Syvänen, Professor and research group leader of Molecular Geriatrics at the same department.

Like two Lego bricks

The method is known as ‘Pretargeted PET’, and the study also used so-called ‘click chemistry’.

“The aim is to label the antibody with radioactivity only once it has already reached the brain. We began by attaching a chemical ‘tag’ to the antibody and injecting it. We then waited three days for the antibody to bind to its target – in our case amyloid beta, the protein strongly associated with Alzheimer’s disease. After that, we injected a small radioactive molecule that reacts with and binds to the tag on the antibody. It can be likened to two Lego bricks that ‘click’ together – hence the term click chemistry,” says Sara Lopes van den Broek.

“The method involves targeting the structure of interest first and then carrying out the imaging more or less immediately after the radioactive substance has been introduced. The antibody, equipped with its chemical tag – or Lego brick – is administered first; this constitutes the pretargeting step,” continues Stina Syvänen.

Opens up the door to other diseases

The method demonstrated by Sara Lopes van den Broek and Stina Syvänen is not limited to amyloid beta and therefore not restricted to Alzheimer’s disease. It is generalisable and could be applied to other brain proteins.

“This technology is not in any way limited to amyloid beta or Alzheimer’s disease. In principle, it can be used for several different target structures,” says Sara Lopes van den Broek, before Stina Syvänen continues:

“With this study, we have shown that the method itself is feasible. This is perhaps the single most important and somewhat surprising finding. The method could be used for other targets in the brain where we currently lack good diagnostic options, for example brain tumours or neuroinflammation.”

Now that you know the method works, are further studies planned?

“Yes. We want to further improve contrast, that is, increase the signal from the target structure in the brain while reducing background signal. Another aspect to explore is how long the tag remains viable in the body. It may be better to perform imaging after seven days rather than the three days used in our study,” says Stina Syvänen.

“Above all, as previously mentioned, it would be interesting to test the method on a different target structure than amyloid beta, to definitively confirm that this technique is generalisable and applicable to diseases beyond Alzheimer’s.”

Robin Widing