Development of PET Radiotracers for Neuroinflammation
Summary
Our aim is to develop novel Positron Emission Tomography (PET) radiotracers for imaging the brain. PET is a non-invasive molecular imaging technique which enables visualization and quantification of various biological targets in vivo (e.g., receptor, enzyme). It is typically the change in either the number or the function of biological targets or biomarkers which is measurable by PET.
Project aims
This information is used primarily to facilitate disease diagnosis or monitoring treatment as well as the drug development. In order to achieve this, a selective and specific PET radiotracer is required which is injectable into subjects. PET radiotracer can be any molecule or biomolecule which is radiolabelled with positron emitting radionuclide (e.g., fluorine-18). Therefore, in our lab, we design, synthesize, radiolabel and evaluate various PET radiotracer candidates for imaging targets/biomarkers in the brain.
In the first step, we identify a biological target of interest, e.g., a receptor which is involved with processes of neuroinflammation. We then focus on the design and chemical synthesis of various analogues from what is identified as the lead chemical structure which has affinity towards the biological target of interest. The design often involves computational tools in predicting chemical properties and is followed by synthesis of derivatives which are then analysed in vitro using various available assays. The next step is radiolabelling of potential PET radiotracers using various radiosynthetic approaches which often involves application of novel methodology. Successfully radiolabelled candidates are evaluated in vivo typically in healthy rodents before they are investigated in disease models.
At present we are investigating three different targets as follows:
- The development of the PET radiotracer for imaging AMPA receptors (AMPAR). AMPAR underlie processes of learning and memory and changes in numbers and/or function of AMPAR, can be quantified by PET. Thus, imaging AMPAR with PET would present a practical tool in assessing brain function. Furthermore, we would like to investigate how changes in AMPA compare with changes in SV2A receptor, a biomarker of synaptic density which is altered in the diseased brain.
- The development of the PET radiotracer for imaging miRNA-223. With PET we would like to establish whether miRNA-223 can be used as a biomarker of neuroinflammation particularly in people with MS. As a large biomolecule, miRNA-223 transport across the blood-brain-barrier presents an additional challenge and our focus is on finding practical tools (e.g., self-penetrating peptide) which can deliver miRNA PET radiotracer into the brain.
- The development of the PET radiotracer for imaging NAAA enzyme to establish whether NAAA can be used as a biomarker of neuroinflammation in people with MS. Starting with the lead structure we are hoping to make structural modifications to improve physicochemical profile.
Design driven and data supported approach in developing new PET probes is hoped to facilitate the bench-to-bedside translation and reduce the failures commonly seen in the development of PET probes.
Contact details
Dr Selena Milicevic Sephton (sms96@medschl.cam.ac.uk) -WBIC