Quantitative Rodent Brain Receptor Imaging

Abstract

Positron emission tomography (PET) is a non-invasive imaging technology employed to describe metabolic, physiological, and biochemical processes in vivo. These include receptor availability, metabolic changes, neurotransmitter release, and alterations of gene expression in the brain. Since the introduction of dedicated small-animal PET systems along with the development of many novel PET imaging probes, the number of PET studies using rats and mice in basic biomedical research tremendously increased over the last decade. This article reviews challenges and advances of quantitative rodent brain imaging to make the readers aware of its physical limitations, as well as to inspire them for its potential applications in preclinical research. In the first section, we briefly discuss the limitations of small-animal PET systems in terms of spatial resolution and sensitivity and point to possible improvements in detector development. In addition, different acquisition and post-processing methods used in rodent PET studies are summarized. We further discuss factors influencing the test-retest variability in small-animal PET studies, e.g., different receptor quantification methodologies which have been mainly translated from human to rodent receptor studies to determine the binding potential and changes of receptor availability and radioligand affinity. We further review different kinetic modeling approaches to obtain quantitative binding data in rodents and PET studies focusing on the quantification of endogenous neurotransmitter release using pharmacological interventions. While several studies have focused on the dopamine system due to the availability of several PET tracers which are sensitive to dopamine release, other neurotransmitter systems have become more and more into focus and are described in this review, as well. We further provide an overview of latest genome engineering technologies, including the CRISPR/Cas9 and DREADD systems that may advance our understanding of brain disorders and function and how imaging has been successfully applied to animal models of human brain disorders. Finally, we review the strengths and opportunities of simultaneous PET/magnetic resonance imaging systems to study drug-receptor interactions and challenges for the translation of PET results from bench to bedside.aligned to a standard reference space for several PET radioligands [63,64]. This enables the use of an automatic normalization and the application of predefined VOIs, minimizing the user-dependent variability. This is particularly important in small-animal PET brain studies, if a voxelbased analysis is performed and small deviations from the standard space will largely impact the results.Quantification Accuracy: Partial-Volume Effect, Spillover, Mass Effect, and Data Reproducibility

A novel antioxidant ergothioneine PET radioligand for in vivo imaging applications

“…Further, the availability of the PET radioligand enables the performance of longitudinal investigations in the same animals. Thus, differences between animals due to inter-individual variations can be controlled for 54 . Overall, we anticipate that this probe will pave the way for the integration of molecular imaging with food biomarkers and biomedical research.…”

Role of Nuclear Imaging to Understand the Neural Substrates of Brain Disorders in Laboratory Animals: Current Status and Future Prospects

“…Some research groups began to develop systems with the aim of visualizing anatomical structures that are much smaller than those of man. The devices used in clinical practice are, in fact, inadequate given the small size of the organs of laboratory animals: indeed, the human brain has a volume of about 1,200 cm 3 , while the rat and mouse brains have, respectively, volumes of about 2 and 0.5 cm 3 , meaning that their brains are ∼600 and 2400 times smaller than the human brain (Herfert et al, 2020) (Figure 1).…”

“…The second proposed technology consists of a small animal PET detector system that surrounds a chamber coupled with a tracking system that allows the position of the rodent's head within the chamber to be measured over time Kyme et al, 2019;Herfert et al, 2020). This system, known as Open-field PET, combines motion-compensated PET with a robotically-controlled animal enclosure to enable simultaneous brain imaging and behavioral recordings in unrestrained rodents.…”

“…Since a small lightweight marker is attached to the forehead of the animal, the motion tracking is able to measure the changing position and orientation of the animal inside the chamber. For image reconstruction, the event-by-event tracking information is used to align the data detected by the PET scanner through the use of a reconstruction algorithm to form a coherent animal body volume (Yao et al, 2012;Herfert et al, 2020). This technique, therefore, allows simultaneous assessment of changes in brain function and behavioral responses to external stimuli in awake, unrestrained animals, with broad applications to behavioral neuroscience research ( Figure 6B).…”

The Neurotransmitter Receptor Architecture of the Mouse Olfactory System

“…This provides a basis for the validation/development of existing/potential positron emission tomography (PET) tracers, a technique with a 10-times lower resolution compared to autoradiography (Bergström et al, 2003). PET as an interdisciplinary, non-invasive in vivo method is used for the study of neuropharmacological drug-receptor targets, particularly in rodent brains (Lancelot and Zimmer, 2010;Herfert et al, 2020). Importantly, the olfactory system seems to play a pivotal role in the neuropathology of neurodegenerative diseases like Alzheimer's or Parkinson's disease.…”