simpetmr · Development of quantification procedures for simultaneous PET-MR data for human brain imaging

Development of quantification procedures for simultaneous PET-MR data for human brain imaging

The discovery and development of drugs for treatment of brain disorders is an enormously challenging process requiring large resources, timelines, and associated costs. Neuroimaging with Positron Emission Tomography (PET) has become a central component of the evaluation of novel drugs for brain disorders by facilitating decision-making already in phase I studies, and thereby provides the possibility to discharge risks very early in the developmental pipeline. With PET, researchers can demonstrate drug penetration and kinetics in the brain and quantify pharmacodynamic effects. This is typically based on experiments where the occupancy of the drug is determined, i.e., the fraction of available binding sites occupied by the drug at a certain dose. Drug occupancy is traditionally estimated by performing multiple PET measurements before and after administration of a drug. Neuroimaging with PET is a remarkably expensive research tool, which often puts a significant strain on the research budget. It also involves exposing research subjects to ionizing radiation, which motivates why we want to minimize the number of PET scans acquired, without sacrificing the knowledge they provide. In this research project, I have developed mathematical models that allows researchers to estimate drug occupancy from a single scan, thereby enabling that the number of PET scans taken are reduced by half. The idea is to administer the drug during an on-going scan (referred to as a displacement scan). As the drug enters the brain, it will displace the tracer molecule, causing a perturbation in the measured signal. With the models I have developed, this perturbation is analysed in such a way that useful information regarding the drug’s binding in brain can be gained. A secondary objective of this research was to develop similar models for simultaneous PET/MR acquisitions. Whereas PET provides information on brain neurochemistry, functional magnetic resonance imaging (fMRI) can provide information on changes in cerebral blood flow that results as a downstream effect from the drug-receptor interaction. Thus, performing displacement scans in a simultaneous PET/MR setting would allow researchers to obtain both these pieces of information at the same time. The overall conclusions from this work is that the mathematical models I have developed constitute a valuable tool for researchers interested in studying the interactions between a drug and brain tissues. They are a set of easy-to-use functions that are anchored in our current understanding of radioligand kinetics in brain tissue. The validation work performed in this project confirm that unbiased and accurate estimates of drug occupancy can be obtained from a single PET scan, given that a sufficiently large dose is given. For smaller doses, although the estimates are unbiased, they come with some uncertainty. Unfortunately, I was not able finalize the development of the models for simultaneous PET/MR acquisitions. At the point in time where this development was about to start, the pandemic was in full bloom. As the health care sector was suffering, access to scanner slots and radioligand production for all non-clinical activities was heavily restricted, and as an effect, I could not perform any PET/MR acquisitions.

Data: CORDIS, © European Union