LOCATE (Leveraging Organoids and Computational Analysis for Tracer Evaluation in PET); next generation individualised Total Body PET scanning

Background

Positron emission tomography (PET) is a powerful imaging technique widely used in medical research, diagnostics, and treatment development, especially for conditions like cancer, heart disease, and neurodegenerative disorders. PET works by introducing a radioactive atom, or radiotracer, into the body, which allows researchers and clinicians to track biological processes in real-time. However, one of the major challenges in PET imaging is the issue of radiotracer breakdown, resulting in radiometabolites—radioactive fragments that are not part of the intended biological signal. These radiometabolites circulate in the body and can confound the PET signal, leading to difficulties in interpreting data accurately and deriving biologically relevant information.

Challenges with Radiometabolites: Traditionally, PET imaging and quantification has been brain-focused. Clinically relevant PET tracers for brain imaging have been specifically designed so that radiometabolites do not cross the blood-brain barrier which has allowed relatively clear PET signals from brain tissue. However, as PET imaging is increasingly being applied to other organs, particularly with the advent of Total-body PET scanners, the challenge of controlling and characterizing radiometabolites has become more prominent (Volpi et al.). Total-body PET technology now allows researchers to image multiple organs simultaneously, making it critical to understand how radiotracers behave throughout the entire body, not just in the brain.

Radiometabolites are primarily processed in the liver, kidneys, and gut (Ghosh et al.), but the extent of tracer breakdown and metabolite production can vary between individuals based on their physiology and the functioning of these organs. For instance, patients with liver or kidney dysfunction may metabolize tracers differently, leading to fewer or more radiometabolites in circulation. This variation highlights the need for a personalized approach to understanding tracer breakdown, as a one-size-fits-all model does not accurately reflect the complexities of human metabolism.

Limitations of Current Approaches: At present, most of what we know about radiometabolites comes from studies using small animal models like mice and rats. These models, however, have significant limitations. First, the use of animals raises ethical concerns and involves procedures like blood sampling, which can be painful and logistically challenging, especially in smaller animals. Additionally, the physiological differences between humans and animals mean that data from animal models may not directly translate to human studies.

Tissue Engineering as an Alternative: To address these limitations, the use of human-derived organoids offers a promising alternative. Organoids are three-dimensional cell culture models made from human cells that can replicate the functions of various organs, including the liver, kidneys, and intestines (Matsui et al.). These organoids can serve as "living phantoms" in PET imaging studies, allowing researchers to observe how radiotracers are metabolized in human tissue, without the need for animal models. Because organoids are metabolically active and reproducible, they can provide critical insights into the role that specific organs play in tracer breakdown and help identify which organ is primarily responsible for the production of radiometabolites for a given tracer.

Computational Modeling to Improve PET Interpretation: The data obtained from organoid studies can be used to develop and inform computational models of radiotracer metabolism. These models, based on compartmental frameworks, can simulate the behaviour of PET tracers in excretory organs like the liver, kidneys, and intestines. By adapting these models, researchers can predict the rate of radiotracer breakdown in individual patients, helping to refine PET image interpretation. These models can account for variations in organ function, offering a more personalized approach to PET data analysis.

Once Total-body PET scanners are widely implemented, it will be possible to validate these computational models in human studies. The models will help predict the behaviour of radiometabolites in individual patient scans, providing a clearer understanding of how pathological changes in liver or kidney function impact tracer metabolism.

Aims

1. Establish organoids as "living phantoms" to investigate radiotracer behaviour.
   • This involves culturing human organoids, exposing them to radiotracers, and imaging them using PET scanners to study how the tracers are metabolized.
2. Develop predictive models for PET tracer breakdown in excretory organs.
   • The goal is to adapt existing compartmental models to describe the metabolic breakdown of PET tracers in human excretory organs, ultimately expanding these models for use in human studies with Total-body PET scanners.

Training Outcomes

The research will provide valuable training in areas such as cell culture and tissue engineering, PET image analysis, and the development of computational models. This project aims to enhance understanding of organ-specific metabolism, improve PET imaging protocols, and offer more accurate interpretations of PET data in clinical settings.

References

Volpi et al. An update on the use of image-derived input functions for human PET studies: new hopes or old illusions? EJNMMI Res., 2024

Ghosh et al., Dealing with PET radiometabolites, EJNMMI Res., 2020

Matsui et al., Human Organoids for Predictive Toxicology Research and Drug Development, Front Genet., 2021