Development of Quantitative PET Imaging Probes for Neuroinflammation

Inflammation is a protective attempt by the immune response of the organism to remove the injurious stimuli as well as to initiate the healing process for the tissue. The inflammatory process is generally beneficial but an inflammation that runs unchecked can also lead to a host of diseases, such as hay fever, atherosclerosis, and rheumatoid arthritis. It is for this reason that inflammation is normally closely regulated by the body.
The brain and spinal cord are considered ?immune privileged? tissues in that they are separated from the rest of the body by a series of endothelial cells known as the blood-brain barrier, which prevent most infections from reaching the vulnerable nervous tissue. For this reason, inflammation in the CNS (Neuroinflammation) is mediated by a unique cell type, microglia. Microglia are part of the non-neuronal part of the cell population in the brain called glia, the other glial cell being the astrocytes and the oligodendrocytes. Quiescent microglia have a ramified morphology as they are constantly moving and analyzing the CNS for damaged neurons, plaques, and infectious agents; whenever an anomaly is detected, microglia enter an active state and undergo several morphological changes including the thickening and retraction of branches, the expression of immunomolecules, the secretion of cytotoxic factors, recruitment molecules and pro-inflammatory signaling molecules.
Microglial activation is therefore present early in any pathological state of the brain and the in-vivo detection of microglial activation is a key diagnostic aim. Besides, microglia chronic activation has also been suggested as a key factor in the inception and/or progression of neurodegenerative diseases like Alzheimer?s disease and Parkinson?s disease. This project aims at delivering an optimal imaging biomarker for microglia using Positron Emission Tomography (PET) technology. PET is a Nuclear Medicine modality that is able to image the distribution of radioactive labelled compounds. The interest in imaging microglia with PET radiotracers is such that more than 50 radiotracers targeting microglia are now proposed world-wide. In the context of this training proposal, we will test the most promising PET microglia tracers, devise appropriate data-processing procedures and metrics that will allow the selection of the optimal marker to be used in the future in diagnostics, research and drug development.

The main aim of this research proposal is to shape a Post-Graduate Training Program in PET Methodology focused on the mathematical modelling of novel TSPO tracers in the normal and diseased brain. The TSPO is consistently expressed in the active microglia population in response to mild, acute or chronic brain injury. Microglia are the resident immuno-competent cell of the central nervous system and, in their active state, release pro-inflammatory molecules that initiate and sustain the immune response. This state is generally referred to as ?Neuroinflammation?. Microglia activity is not only regarded as the most sensitive marker of brain disease but it has also been proposed as pathogenic agent in neurodegenerative diseases, Alzheimer?s and Parkinson?s disease in particular. In-vivo TSPO imaging using PET started more than 20 years ago using 11C-PK11195, a positron emitter labelled antagonist for the TSPO but, because of the poor sensitivity of this tracer, research for novel TSPO tracers has surged in the last 5 years with more than 50 new PET TSPO-markers under various stages of clinical validation. It is because of this exceptionally large number of novel tracers and the importance of neuroinflammation for the clinical neurosciences that we define as the main objective of the proposed training program the identification of the optimal TSPO PET probe(s) and of the associated quantitative methodology.
The training program is proposed in three phases. The first one (3 months) will provide the trainee with the basic knowledge on PET methodology. The second phase, (21 months) will consist in a set of 3 months supervised research projects, that will look at various aspects(biological/pathology/chemical/kinetic) of novel TSPO ligands and supply data to a metric (the elaboration of which is one of the research questions) that will inform on the best amongst all candidates and on its quantification procedure. The last phase of the research program (24 months) will be carried out independently by the trainee in the field of TSPO data quantification and will make use of the wealth of clinical and pre-clinical data available at the participating PET centres. We believe that this proposal has unique strengths in the form and content of the training program, in the relevance of the theme for the neurosciences, in the quality and breadth of experience in PET Methodology of the proponents, and the strong academic/industrial partnership (Imperial/GSK) that characterizes the environment.