Handbook of Small Animal Imaging

Preclinical Imaging, Therapy, and Applications

George C. Kagadis, Nancy L. Ford, Dimitrios N. Karnabatidis, George K. Loudos, George C. Kagadis, Nancy L. Ford, Dimitrios N. Karnabatidis, George K. Loudos

• Publisher: CRC Press
• Year: 2018
• eBook ISBN: 9781315360423
• Edition: 1
• Topic: Medicine
• Subtopic: Radiology, Radiotherapy & Nuclear Medicine

The use of small animal models in basic and preclinical sciences constitutes an integral part of testing new pharmaceutical agents prior to their application in clinical practice. New imaging and therapeutic approaches need to be tested and validated first in animals before application to humans.

Handbook of Small Animal Imaging: Preclinical Imaging, Therapy, and Applications collects the latest information about various imaging and therapeutic technologies used in preclinical research into a single source. Useful to established researchers as well as newcomers to the field, this handbook shows readers how to exploit and integrate these imaging and treatment modalities and techniques into their own research.

The book first presents introductory material on small animal imaging, therapy, and research ethics. It next covers ionizing radiation and nonionizing radiation methods in small animal imaging, hybrid imaging, and imaging agents. The book then addresses therapeutic research platforms and image quantification, explaining how to ensure accurate measurements of high-quality data. It concludes with an overview of many small animal imaging and therapy applications that demonstrate the strength of the techniques in biomedical fields.

Section VIII

Applications

Chapter 25 Small Animal Imaging and Therapy: How They Affect Patient Care

Chapter 26 Applications for Drug Development

Chapter 27 Imaging of Intracellular Targets

Chapter 28 Imaging of Cell Trafficking and Cell Tissue Homing

Chapter 29 Imaging of Cardiovascular Disease

Chapter 30 Imaging Angiogenesis

Chapter 31 Imaging of Hypoxia, Apoptosis, and Inflammation

Chapter 32 Vessel Wall Imaging

25

Small Animal Imaging and Therapy
How They Affect Patient Care

Lawrence W. Dobrucki

25.1 Small Animal Imaging in the Development of a New Generation of Theranostics

25.1.1 Clinical Imaging Modalities

25.1.1.1 Nuclear Imaging Modalities

25.1.1.2 X-Ray Computed Tomography

25.1.1.3 Magnetic Resonance

25.1.1.4 Optical Imaging

25.1.2 Traditional Imaging Agents

25.1.3 Theranostic Approaches

25.2 Development of Molecular Imaging Probes Used in the Clinic

25.2.1 Use of Animal Models in Target Validation

25.2.2 Practical Aspects of Development of New Molecular Imaging Probes

25.3 Future Directions

References

Over the past few decades, advances in life sciences, such as molecular biology, genomics, and proteomics, and the recent growth in the instrumentation and computational sciences, have stimulated the development of novel strategies focused on early detection and treating disease based on an individual’s unique profile, an approach called “individualized medicine.”

The growth of individualized medicine, which includes the development of personalized treatment regimes, will be aided by research efforts that provide better understanding of molecular events associated with normal and pathological processes. This research will contribute to the overall knowledge of the biochemical mechanisms that initiate the disease process, will allow for the identification of disease subtypes and will aid in predicting patient’s response to the therapy. However, the described process of advancing patient care through individualized medicine is quite complex and slow. Through recent developments in imaging technology and advances in genomic medicine, it became evident that molecular imaging approaches including preclinical research bring a promise to accelerate, simplify, and reduce the costs of delivering improved health care to patients and has a great potential to facilitate the implementation of individualized medicine in clinics.

During recent decades, the translation of preclinical imaging approaches to clinical trials and patient use provided strong evidence that current clinical imaging applications have been proven to be effective to diagnose diseases such as cancer, neurological disorders, and cardiovascular disease in their initial stages, which permitted effective treatment associated with reduced morbidity and mortality. In addition, it was demonstrated that noninvasive imaging of therapeutic response reduced patients’ exposure to toxic and ineffective treatments and allowed for early inclusion of alternative therapeutic interventions. Finally, these imaging approaches allowed the development of molecularly targeted treatments of cancer and certain endocrine disorders.

Critical reviews of current clinical applications of molecular imaging and their challenges have aided to identify emerging opportunities in molecular imaging, which should be addressed in the relatively near future. These opportunities include understanding the relationship between brain chemistry and behavior, understanding the metabolism and pharmacology of new drugs, assessment of the efficacy of new therapeutics and other forms of treatment allowing for quick introduction to clinical practice, and employment of targeted imaging or theranostic approaches for clinical use. In addition, these current challenges include the development of new technology platforms such as integrated microfluidic chips that would accelerate and reduce the costs associated with the synthesis and evaluation of novel molecular imaging probes and the development of higher resolution, higher sensitivity imaging instruments to detect and quantify disease processes faster and more accurately.

In spite of these exciting possibilities to improve patient health care through the translation of preclinical imaging approaches, the deteriorating infrastructure, loss of federal research support, and long and inefficient approval process for new imaging probes are jeopardizing the advancement of molecular imaging approaches. Understanding these challenges and careful systemic planning on how to address them is critical to revitalize the field to realize its potential.

25.1 SMALL ANIMAL IMAGING IN THE DEVELOPMENT OF A NEW GENERATION OF THERANOSTICS

25.1.1 CLINICAL IMAGING MODALITIES

New diagnostic and therapeutic agents are typically complex compounds for which biodistribution and pharmacokinetic profiles in vivo are difficult to assess. Therefore, multiple imaging approaches have been proposed to model targeted uptake and predict pharmacokinetics in vivo. These noninvasive imaging strategies have become essential tools used in basic and applied research. Typical workflow allows for dynamic imaging to assess the biodistribution of a studied probe or therapeutic agent in the same animal at different time points or stages of disease. Performing imaging studies in the same animal is cost-effective and minimizes variations between individuals, which results in enhanced reproducibility and repeatability as compared to traditional methods based on postmortem investigations.

Small animal imaging provides noninvasive means to assess biodistribution and pharmacokinetics of new experimental drugs and imaging probes in physiologically relevant environments in vivo. Intense development of new instrumentation and novel imaging strategies resulted in the availability of small animal dedicated imaging systems, which can be used to produce information about anatomical structures and physiological function. Novel trends in hybridization characterized by the combination of two or more imaging modalities led to the design and construction of multimodal imaging systems, which provided the most accurate information on the function of the studied agents with excellent anatomical references (Dobrucki and Sinusas 2005a,b,c).

Over the past three decades, multiple new imaging modalities have been developed but only few are currently used in both preclinical and clinical researches involving molecular imaging agents, including nuclear techniques (positron emission tomography [PET] and single photon emission computed tomography [SPECT]), x-ray computed tomography, magnetic resonance imaging, and optical imaging. The optimal choice of the most suitable imaging application for a certain study depends on the availability of both the instrumentation and imaging probe and prioritization of requested features. Detailed description of each imaging modality with the focus on their strengths and weaknesses is beyond the scope of this chapter; therefore, the readers are directed to the relevant chapters of this book or a few excellent recently published reviews (Bengel 2009; Dobrucki and Sinusas 2010; Mitsos et al. 2012).

25.1.1.1 Nuclear Imaging Modalities

Nuclear imaging includes SPECT and PET that belongs to clinical imaging modalities, which have been proved to provide excellent sensitivity (in the picomolar range), good temporal resolution (from seconds to minutes), and reasonable spatial resolution (one to few millimeters) (Basu et al. 2011).

In PET imaging, positrons emitted from an unstable atomic nucleus undergo an annihilation process with electrons, which results in the production of two gamma photons of 511 keV energy, separated by 180° and detected by a ring of gamma detectors located around the imaged object. The information about the location of the annihilation process derived from the detection of two 511 keV photons is then used to measure radioactive tracer accumulation in the tissue of interest or its consumption over time.

The major strength of PET imaging is that radionuclides such as carbon-11, nitrogen-13, or oxygen-15 can be incorporated in the molecule with minimal interference to the function of pharmaceuticals. This allows for developing radiolabeled probes, which are chemically almost identical to the parent compounds. This strategy has been successfully employed to develop PET tracers, which can pass the blood–brain barrier and can be used for imaging brain function (Judenhofer et al. 2008; Mariani et al. 2010).

PET imaging is also advantageous when considering its superior sensitivity, practically limitless penetration depth, and its ability for high-temporal resolution dynamic imaging which can provide useful information on pharmacokinetic parameters and can be used in compartmental modeling of probe’s cellular uptake and washout rates.

One important disadvantage of PET is its fundamental limitation in achieving very high-spatial resolution, which is associated with the fact that the localization of positron emission is not the same as the place of annihilation and strongly depends on both the energy of emitted positron and the electron density of the tissue.

The labeling of PET pharmaceuticals can be complicated and due to the short half-life of PET isotopes, the presence of an on-site production cyclotron is required. Among the clinically available radioisotopes, only fluorine-18 has an adequate half-life (∼2 h) that allows for required delivery times to be hours, not minutes. Other radioisotopes such as copper-64 (∼12.7 h half-life) and zirconium-89 (∼3.3 days half-life) are currently evaluated in preclinical models with the promise to be translated to clinical use in the near future (Wadas et al. 2007; De Silva et al. 2012; Zeng et al. 2012).

SPECT imaging is historically an older technique than PET and is based on the detection of gamma radiation emitted from an unstable atomic nucleus. Typically, an animal or patient injected with a SPECT radiopharmaceutical is imaged from several angles (projections), which enables 3D reconstruction of an image and further image processing and analysis. Radioisotopes used in SPECT imaging are characterized by their specific emission spectra, which allow for simultaneous multiple isotope imaging. Also, their relatively long half-lives (hours to days) allow for longitudinal imaging studies for up to several weeks with single administration of the studied radiopharmaceutical. Since different radioisotopes have different physicochemical properties, labeling the molecules or bioactive agents requires access to the radiochemistry resources and the knowledge of traditional chemistry. Also, many SPECT isotopes (technetium-99m, indium-111, or radioactive iodine isotopes such as iodine-125 and iodine-123) need to be chelated before labeling the parent molecule. This process can increase the molecular weight of the target molecule, may change ...

Table of contents

• Cover
• Half Title
• Title Page
• Copyright Page
• Dedication
• Table of Contents
• Series Preface
• Preface
• Editors
• Contributors
• Section I—Introduction to Small Animal Imaging, Therapy, and Applications
• Section II —Small Animal Imaging: Ionizing Radiation
• Section III—Small Animal Imaging:Nonionizing Radiation
• Section IV—Hybrid Imaging
• Section V—Imaging Agents
• Section VI—Therapeutic Research Platforms
• Section VII—Image Quantification
• Section VIII—Applications
• Index