Application of Small Animal PET in Biomedical Research
Small animal PET (Positron Emission Tomography) can determine the spatial distribution, quantity, and temporal changes of positron-emitting radiotracers in the same living animal. Each animal can be repeatedly studied, serving as its own control, which eliminates inter-subject variability and significantly reduces the number of animals required. Another advantage of small animal PET scanners is that they can unify animal experimental results with clinical research. Therefore, this non-invasive dynamic imaging technique not only provides new tools for drug development and research but also can be used in the study of animal models of human diseases, gene expression imaging, and other areas.
1.1 Application of Small Animal PET in Drug Discovery and Development
Currently, the development of a new class I drug still requires about 12-15 years and costs approximately $2.5 billion. The completion of the human genome sequencing has identified numerous potential biological targets for drug action, creating new conditions for modern innovative drug research. This has led to a significant increase in the number of lead compounds. However, despite their activity in vitro, there is no suitable method to prove their efficacy in vivo. This is a major bottleneck in drug development, and there is a pressing need for a rational process that bridges the gap from preclinical to clinical studies, shortening the drug development timeline and reducing costs. The emergence of non-invasive dynamic imaging techniques like PET (both clinical and animal PET) will effectively address this challenge and greatly accelerate the drug development process.
1.1.1 Positron-Emitting Radiotracers Used in Drug Research and Development
The positron-emitting radiotracers used in PET for drug research and development are generally categorized into four types:
Direct Labeling of Drugs with Positron-Emitting Isotopes: Most drug molecules contain carbon atoms, making ^11C the most commonly used positron-emitting isotope. ^18F can replace fluorine or hydrogen atoms in drugs, and ^13N can also be used to label certain drugs. These isotopes are used to study the biodistribution and other pharmacokinetic parameters, as well as pharmacodynamic effects of drugs.
Labeling of Endogenous or Essential Compounds or Analogs: For example, ^15O-H2O is used to study regional blood flow; ^18F-FDG and ^18F-FLT are analogs of glucose and thymidine, respectively, reflecting the body’s glucose metabolism or DNA replication status. By observing the effects of drugs on these radiotracers, researchers can study the impact of drugs on physiological and biochemical parameters.
Labeling of Ligands and Antibodies: Positron-emitting isotopes labeled ligands have a high binding affinity to specific receptors, which can be used to measure the distribution, concentration, and characteristics of specific receptors in the body, as well as to study the effects of unlabeled drugs on these receptors. Positron-emitting isotopes labeled antibodies or antibody fragments can be used to locate and monitor tumors, observe whether antibodies can specifically bind to tumor cell receptors, and study the distribution, metabolism, and excretion of antibodies in animals.
Labeling of Biomarkers: These biomarkers can interact with components of biological pathways and are used to detect the status of specific pathways, such as the dopaminergic pathway in the central nervous system.
1.1.2 Application of Small Animal PET in Drug Research and Development
Small animal PET can complete in vivo animal experiments in the early stages of drug development, monitoring pharmacokinetics, pharmacodynamics, and other relevant biological information. Small animal PET can be used to screen lead compounds from candidate drugs and simultaneously obtain pharmacokinetic parameters of candidate drugs in various tissues and organs. Additionally, knowing the occupancy of drugs at their target sites can help determine the initial dose for subsequent human studies. The successful development of small animal PET also provides opportunities for evaluating drugs that are currently in use.
2 Application of Small Animal PET in Human Disease Research
One major advantage of using small animal PET to study animal models is the ability to determine the temporal and spatial distribution and changes of positron-emitting radiotracers in the same experimental animal. Experiments can be repeated on the same animal over several days, weeks, or months. This is particularly beneficial for studying chronic disease models or monitoring the effects of a series of interventions. Moreover, the in vivo imaging parameters used are the same as those used in clinical PET, allowing for direct comparisons. Therefore, small animal PET can serve as a platform for studying human diseases, accelerating the transition from animal research to clinical studies.
1.2.1 Application of Small Animal PET in Neurological Disease Research
Currently, the spatial resolution of small animal PET is sufficient to clearly identify structures within the animal brain, such as the thalamus, striatum, and cortical substructures. Using small animal PET for in vivo imaging of animal models provides unique value in the study of cerebrovascular diseases, Parkinson’s disease, Alzheimer’s disease, brain tumors, and epilepsy.
1.2.2 Application of Small Animal PET in Cancer Research
Tumor models may show significant differences between two animals, but one of the advantages of small animal PET is the ability to repeat experiments on the same animal, thereby avoiding such differences. In tumor animal models, tumors are generally implanted in the limbs, shoulders, or backs of animals, where the background values are much lower than those of major organs, making quantitative analysis easier. Additionally, small animal PET can effectively observe and monitor the invasion and spread of metastatic tumors.
1.2.3 Application of Small Animal PET in Cardiovascular Disease Research
The hearts of rats and mice are relatively small, but the spatial resolution of currently developed small animal PET systems has greatly improved, allowing for the measurement of glucose metabolism (^18F-FDG) and myocardial blood flow (^13N-ammonia) in models of myocardial ischemia and infarction. These studies demonstrate the potential of small animal PET in cardiovascular disease research.
1.3 Application of Small Animal PET in Gene Expression Imaging
In recent years, with the development and integration of related disciplines such as molecular biology and molecular genetics, gene diagnosis and gene therapy have advanced rapidly. Monitoring the localization and expression levels of transfected genes, gene imaging is the most effective method. The use of PET for in vivo gene expression imaging in animals and humans has generated widespread interest among researchers. Gene imaging with PET requires PET reporter genes and positron-emitting probes that match the reporter genes. Currently, there are two main types of reporter gene systems: enzyme-mediated reporter genes, where the reporter gene is transcribed into an enzyme product that traps the reporter probe and converts it into a detectable metabolite, resulting in signal amplification within the cell and allowing the measurement of the location, quantity, and duration of reporter gene expression; and receptor-mediated reporter genes, where the reporter gene is transcribed into receptor proteins located on the cell surface, inside, or outside the cell, and the binding of the receptor to the reporter probe (ligand) produces a signal, enabling the measurement of the location, quantity, and duration of reporter gene expression.